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| United States Patent |
5,716,975
|
|
Bue-Valleskey
, et al.
|
February 10, 1998
|
Compounds useful as hypoglycemic agents and for treating Alzheimer's
disease
Abstract
Provided are methods for treating hyperglycemia and Alzheimer's disease
utilizing certain rhodanine derivatives. Certain of the rhodanine
derivatives utilized in the instant methods are novel and, accordingly,
such compounds and pharmaceutical formulations thereof are also provided.
| Inventors:
|
Bue-Valleskey; Juliana M. (Indianapolis, IN);
Hunden; David C. (Carmel, IN);
Jones; Charles D. (Indianapolis, IN);
Panetta; Jill A. (Zionsville, IN);
Shaw; Walter N. (Indianapolis, IN)
|
| Assignee:
|
Eli Lilly and Company (Indianapolis, IN)
|
| Appl. No.:
|
470822 |
| Filed:
|
June 6, 1995 |
| Current U.S. Class: |
514/369; 548/183 |
| Intern'l Class: |
C07D 277/31; A61K 031/125 |
| Field of Search: |
548/183
514/369
|
References Cited
U.S. Patent Documents
| 4287200 | Sep., 1981 | Kawamatsu et al. | 424/270.
|
| 4376777 | Mar., 1983 | Kawamatsu et al. | 424/270.
|
| 4387101 | Jun., 1983 | Kawamatsu et al. | 424/270.
|
| 4461902 | Jul., 1984 | Kawamatsu et al. | 548/183.
|
| 4464382 | Aug., 1984 | Tanouchi et al. | 424/270.
|
| 4552891 | Nov., 1985 | Ho et al. | 514/443.
|
| 4617312 | Oct., 1986 | Schnur | 514/369.
|
| 4636516 | Jan., 1987 | Kubo et al. | 514/365.
|
| 4703052 | Oct., 1987 | Eggler et al. | 514/337.
|
| 4714765 | Dec., 1987 | Ogawa et al. | 548/183.
|
| 4863923 | Sep., 1989 | Ho et al. | 514/443.
|
| 4948900 | Aug., 1990 | Iijima et al. | 548/183.
|
| 4971996 | Nov., 1990 | Shiraishi | 514/521.
|
| 4997948 | Mar., 1991 | Zask et al. | 548/183.
|
| 5116855 | May., 1992 | Inoui et al. | 514/369.
|
| 5158966 | Oct., 1992 | Lafferty | 514/369.
|
| 5208250 | May., 1993 | Cetenko | 514/364.
|
| 5356917 | Oct., 1994 | Panette | 514/364.
|
| Foreign Patent Documents |
| 045165 | Feb., 1982 | EP | .
|
| 193256 | Sep., 1986 | EP | .
|
| 208420 | Jan., 1987 | EP | .
|
| 211670 | Feb., 1987 | EP | .
|
| 212617 | Apr., 1987 | EP | .
|
| 237138 | Sep., 1987 | EP | .
|
| 343643 | Nov., 1989 | EP | .
|
| 391644 | Oct., 1990 | EP | .
|
| 398179 | Nov., 1990 | EP | .
|
| 434394 | Jun., 1991 | EP | .
|
| 449216 | Oct., 1991 | EP | .
|
| 569777 | Nov., 1993 | EP | .
|
| 1038050 | Sep., 1958 | DE | .
|
| 226617 | Sep., 1968 | SU | .
|
| 2249788 | May., 1992 | GB | .
|
Other References
Teuber et al., Liebigs Ann. Chem., 757 (1978).
Katsumi et al., Chem. Pharm. Bull., 34(4) 1619 (1986).
Chakrabarti et al., Tetrahedron, 2781 (1969).
Roggero et al., Bull. De La Societe Chimique De France 11, 4021 (1971).
Patent Abstracts of Japan, 11(232) (C-437) 2679! 1987, abstracting JP
62-45553.
Allan et al., J. Org. Chem., 23, 112 (1958).
Fujita et al., Diabetes 32, 804 (1983).
Shoda et al., Chem. Pharm. Bull., 30(10), 3563 (1982).
Shoda et al., Chem. Pharm. Bull., 30(10), 3580 (1982).
Shoda et al., Chem. Pharm. Bull., 32(6), 2267 (1984).
Tomisawa et al., Chem. Pharm. Bull., 34(2), 701 (1986).
Isomura et al., Chem. Pharm. Bull., 32(1), 152 (1984).
Patent Abstracts of Japan, 11(206) (C-433) 2653! 1987, abstracting JP
62-29570.
Derwent Abstracts, 87-076383/11, abstracting J6 2029-579A (1991).
Chemical Abstracts, vol. 116, No. 20983q (1992).
Chemical Abstracts, 69, No. 42531d (1968).
Agarwal et. al., Curr Sci, 49(12) 455 (1980).
Husain et al., Acta Pharma. Jugoslav 36(3) 311 (1986).
Derwent Abstracts 91-031957, abstracting JP-A-2 300,119, 1991.
Mohan et al., Indian Drugs, 21/3, 90 (1983).
|
Primary Examiner: Gerstl; Robert
Attorney, Agent or Firm: Palmberg; Arleen, Taylor; Douglas J.
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a division of application Ser. No. 08/213,651, filed
Mar. 16, 1994, now U.S. Pat. No. 5,523,314, which is a Continuation in
Part application of application Ser. No. 07/943,353 filed Sep. 10, 1992
abandoned.
Claims
We claim:
1. The compound
5-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene!-4-oxo-2-thioxo-3
-thiazolidine acetic acid or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical formulation comprising a compound of claim 1 associated
with at least one pharmaceutically acceptable carrier, diluent or
excipient therefor.
3. The compound
5-3,5-bis(1-methylpropyl)-4-hydroxyphenyl)methylene!-4-oxo-2-thioxo-3-th
iazolidine acetic acid or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical formulation comprising a compound of claim 3 associated
with at least one pharmaceutically acceptable carrier, diluent or
excipient therefor.
5. The compound
5-(3,5-dichloro-4-hydroxyphenyl)methylene!-2-thioxo-4-thiazolidinone or a
pharmaceutically acceptable salt thereof.
6. A pharmaceutical formulation comprising a compound of claim 5 associated
with at least one pharmaceutically acceptable carrier, diluent or
excipient therefor.
7. The compound
5-3-ethoxy-4-hydroxy-5-(methylthiophenyl)phenyl!methylene!-4-oxo-2-thiox
o-3-thiazolidine acetic acid or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical formulation comprising a compound of claim 7 associated
with at least one pharmaceutically acceptable carrier, diluent or
excipient therefor.
9. The compound
5-3-(1,1-dimethylethyl!-4-hydroxy-5-(methylthiophenyl)phenyl!methylene!-
2-thioxo-4-thiazolidinone or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical formulation comprising a compound of claim 9
associated with at least one pharmaceutically acceptable carrier, diluent
or excipient therefor.
11. The compound
5-(3-ethoxy-4-hydroxyphenyl)methylene!-2-thioxo-3-methyl-4-thiazolidinone
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical formulation comprising a compound of claim 11
associated with at least one pharmaceutically acceptable carrier, diluent
or excipient therefor.
13. The compound
5-(3-ethoxy-4-hydroxyphenyl)methylene!-2-thioxo-3-dimethylamino-4-thiazol
idinone or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical formulation comprising a compound of claim 13
associated with at least one pharmaceutically acceptable carrier, diluent
or excipient therefor.
15. The compound
5-3-(1,1-dimethylethyl)-4-hydroxyphenyl!methylene!-2-thioxo-3-methyl-4-t
hiazolidinone or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical formulation comprising a compound of claim 15
associated with at least one pharmaceutically acceptable carrier, diluent
or excipient therefor.
Description
BACKGROUND OF THE INVENTION
Diabetes mellitus is a systemic disease characterized by disorders in the
metabolism of insulin, carbohydrates, fats and proteins, and in the
structure and function of blood vessels. The primary symptom of acute
diabetes is hyperglycemia, often accompanied by glucosuria, the presence
in urine of large amounts of glucose, and polyuria, the excretion of large
volumes of urine. Additional symptoms arise in chronic or long standing
diabetes. These symptoms include degeneration of the walls of blood
vessels. Although many different organs are affected by these vascular
changes, the eyes and kidneys appear to be the most susceptible. As such,
long-standing diabetes mellitus, even,when treated with insulin, is a
leading cause of blindness.
There are two recognized types of diabetes. Type I diabetes is of juvenile
onset, ketosis-prone, develops early in life with much more severe
symptoms and has a near-certain prospect of later vascular involvement.
Control of this type of diabetes is difficult and requires exogenous
insulin administration. Type II diabetes mellitus is of adult onset,
ketosis-resistant, develops later in life, is milder and has a more
gradual onset.
One of the most significant advancements in the history of medical science
came in 1922 when Banting and Best demonstrated the therapeutic effects of
insulin in diabetic humans. However, even today, a clear picture of the
basic biochemical defects of the disease is not known, and diabetes is
still a serious health problem. It is believed that two percent of the
United States' population is afflicted with some form of diabetes.
The introduction of orally effective hypoglycemic agents was an important
development in the treatment of hyperglycemia by lowering blood glucose
levels. Oral hypoglycemic agents are normally used in the treatment of
adult onset diabetes.
A variety of biguanide and sulfonylurea derivatives have been used
clinically as hypoglycemic agents. However, the biguanides tend to cause
lactic acidosis and the sulfonylureas, though having good hypoglycemic
activity, require great care during use because they frequently cause
serious hypoglycemia and are most effective over a period of ten years.
In Chemical & Pharmaceutical Bulletin, 30, 3563 (1982), Chemical &
Pharmaceutical Bulletin, 30, 3580 (1982) and Chemical & Pharmaceutical
Bulletin, 32, 2267 (1984), reference is made to a variety of
thiazolidinediones which have blood glucose and lipid lowering activities.
Antidiabetic activity of ciglitazone was also reported in Diabetes, 32,
804 (1983). However, these compounds have proven difficult to use because
of insufficient activities and/or serious toxicity problems.
Furthermore, Alzheimer's disease, a degenerative disorder of the human
brain, continues to afflict more and more persons throughout the world.
Such disease results in progressive mental deterioration manifested by
memory loss, confusion, disorientation and the concomitant loss of
enjoyment of life associated therewith. At the present time there is no
scientifically recognized treatment for Alzheimer's disease. Because of
this, and because of the debilitating effects of the disease, there
continues to exist an urgent need for effective treatments.
The present invention relates to a series of hypoglycemic agents which are
capable of lowering blood glucose levels in mammals. Accordingly, one
object of the present invention is to provide compounds having excellent
hypoglycemic activity. The hypoglycemic agents of the present invention
are believed to have minimal toxicological effects. It is, therefore,
believed that the compounds of the present invention may be very useful
for treating diabetes.
The present invention also relates to a series of compounds having
cathepsin inhibitory activity. As will be discussed more fully below,
compounds capable of inhibiting cathepsin (and, in particular, cathepsin
D) may be useful for treating Alzheimer's disease. Accordingly, a further
object of the present invention is to provide compounds which can be used
to treat Alzheimer's disease.
Other objects, features and advantages of the present invention will become
apparent from the subsequent description and the appended claims.
SUMMARY OF THE INVENTION
The present invention provides a method of reducing blood glucose
concentrations in mammals comprising administering a therapeutically
effective amount of a compound of formula (I)
##STR1##
wherein: Ar is (i) phenyl, (ii) phenyl substituted with from one to three
substituents independently selected from C.sub.1 -C.sub.8 alkyl, C.sub.1
-C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkylthio, trifluoromethyl, C.sub.1
-C.sub.4 alkylphenyl, phenyl, NO.sub.2, F, Cl, hydroxy, phenoxy, C.sub.1
-C.sub.4 alkyloxyphenyl, thiophenyl, C.sub.1 -C.sub.4 alkylthiophenyl,
--COOR.sup.7, --N(R.sup.7)SO.sub.2 R.sup.7 or --N(R.sup.7).sub.2, where
each R.sup.7 is independently hydrogen or C.sub.1 -C.sub.6 alkyl, (iii) 1-
or 2-naphthyl, (iv) 2- or 3-benzofuranyl, (v) 2- or 3-benzothiophenyl,
(vi) 2-, or 3-thienyl, (vii) 2-, 3- or 4-pyridyl, (viii) 2- or 3-furanyl,
(ix) 1,3-benzodioxanyl, (x) substituted 1,3-benzodioxanyl, (xi)
quinolinyl, (xii) 2- or 3-indolyl or (xiii) N-substituted 2- or 3-indolyl;
R.sup.1 is C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.4 alkylphenyl, hydrogen,
phenyl or phenyl substituted with one or two substituents independently
selected from Cl, Br, F, I, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4
alkoxy, hydroxy, trifluoromethyl, --NH.sub.2, --NH(C.sub.1 -C.sub.4
alkyl), --N(C.sub.1 -C.sub.4 alkyl).sub.2 or C.sub.1 -C.sub.4 alkylthio;
R.sup.2 and R.sup.3 are each hydrogen or when taken together form a bond;
R.sup.4 and R.sup.5 are each hydrogen or when taken together are .dbd.S, or
when one of R.sup.4 and R.sup.5 is hydrogen, the other is --SCH.sub.3 ;
R.sup.6 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl,
C.sub.2 -C.sub.6 alkenyl, --SO.sub.2 CH.sub.3, or --(CH.sub.2).sub.p --Y
where p is 0, 1, 2, or 3 and Y is cyano, --OR.sup.8,
##STR2##
tetrazolyl, --NR.sup.10 R.sup.11, --SH, C.sub.1 -C.sub.4 alkylthio, or
##STR3##
where R.sup.8 is hydrogen, C.sub.1 -C.sub.4 alkyl or
##STR4##
R.sup.9 is hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy,
hydroxy or NH.sub.2, and R.sup.10 and R.sup.11 are each independently
hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2
-C.sub.6 alkynyl, phenyl, C.sub.1 -C.sub.4 alkylphenyl, --(CH.sub.2).sub.q
OH, --(CH.sub.2).sub.q N(C.sub.1 -C.sub.4 alkyl).sub.2, or
--(CH.sub.2).sub.q S(C.sub.1 -C.sub.4 alkyl), where q is an integer from 1
to 6, both inclusive, or R.sup.10 and R.sup.11, taken together with the
nitrogen atom to which they are attached, form a morpholinyl, piperidinyl,
piperizinyl, or N-methylpiperazinyl ring; and
m is 0, 1, or 2; with the provisos that
Ar cannot be phenyl substituted solely with one chloro substituent at the
4-position of the phenyl ring;
Ar cannot be phenyl substituted with a COOH moiety at the 2-position of the
phenyl ring;
when Ar is phenyl substituted with two ethoxy moieties at the 3- and
4-positions of the phenyl ring, R.sup.1 must be hydrogen;
Ar cannot be phenyl substituted solely with two hydroxy substituents; and
when R.sup.4 and R.sup.5 are each hydrogen, R.sup.6 cannot be C.sub.1
-C.sub.6 alkyl,
or a pharmaceutically acceptable salt thereof, to a mammal in need of
having its blood glucose concentration reduced.
The present invention also provides a method of treating Alzheimer's
disease in a mammal suffering from or susceptible to such disease
comprising administering a therapeutically effective amount of a compound
of formula (Ia)
##STR5##
wherein: Ar is (i) phenyl, (ii) phenyl substituted with from one to three
substituents independently selected from C.sub.1 -C.sub.8 alkyl, C.sub.1
-C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkylthio, trifluoromethyl, C.sub.1
-C.sub.4 alkylphenyl, phenyl, NO.sub.2, F, Cl, hydroxy, phenoxy, C.sub.1
-C.sub.4 alkyloxyphenyl, thiophenyl, C.sub.1 -C.sub.4 alkylthiophenyl,
--COOR.sup.7, --N(R.sup.7)SO.sub.2 R.sup.7 or --N(R.sup.7).sub.2, where
each R.sup.7 is independently hydrogen or C.sub.1 -C.sub.6 alkyl or (iii)
1- or 2-naphthyl;
R.sup.1 is C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.4 alkylphenyl, hydrogen,
phenyl or phenyl substituted with one or two substituents independently
selected from Cl, Br, F, I, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4
alkoxy, hydroxy, trifluoromethyl, --NH.sub.2, --NH(C.sub.1 -C.sub.4
alkyl), --N(C.sub.1 -C.sub.4 alkyl).sub.2 or C.sub.1 -C.sub.4 alkylthio;
R.sup.2 and R.sup.3 are each hydrogen or when taken together form a bond;
R.sup.4 and R.sup.5 are each hydrogen or when taken together are .dbd.S, or
when one of R.sup.4 and R.sup.5 is hydrogen, the other is --SCH.sub.3 ;
R.sup.6 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl,
C.sub.2 -C.sub.6 alkenyl, --SO.sub.2 CH.sub.3, or --(CH.sub.2).sub.p --Y
where p is 0, 1, 2, or and Y is cyano, --OR.sup.8,
##STR6##
tetrazolyl, --NR.sup.10 R.sup.11, --SH, C.sub.1 -C.sub.4 alkylthio, or
##STR7##
where R.sup.8 is hydrogen, C.sub.1 -C.sub.4 alkyl or
##STR8##
R.sup.9 is hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy,
hydroxy or NH.sub.2, and R.sup.10 and R.sup.11 are each independently
hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2
-C.sub.6 alkynyl, phenyl, C.sub.1 -C.sub.4 alkylphenyl, --(CH.sub.2).sub.q
OH, --(CH.sub.2).sub.q N(C.sub.1 -C.sub.4 alkyl).sub.2, or
--(CH.sub.2).sub.q S(C.sub.1 -C.sub.4 alkyl), where q is an integer from 1
to 6, both inclusive, or R.sup.10 and R.sup.11, taken together with the
nitrogen atom to which they are attached, form a morpholinyl, piperidinyl,
piperizinyl, or N-methylpiperazinyl ring; and
m is 0, 1, or 2;
or a pharmaceutically acceptable salt thereof, to a mammal in need of such
treatment.
Certain of the compounds which can be employed in the methods of the
present invention are novel. As such, the present invention also provides
novel compounds of the formula (II)
##STR9##
wherein: Ar is (i) phenyl, (ii) phenyl substituted with from one to three
substituents independently selected from C.sub.1 -C.sub.8 alkyl, C.sub.1
-C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkylthio, trifluoromethyl, C.sub.2
-C.sub.4 alkylphenyl, NO.sub.2, F, Cl, phenoxy, C.sub.1 -C.sub.4
alkyloxyphenyl, thiophenyl, C.sub.1 -C.sub.4 alkylthiophenyl,
--COOR.sup.7, --N(R.sup.7)SO.sub.2 R.sup.7 or --N(R.sup.7).sub.2, where
each R.sup.7 is independently hydrogen or C.sub.1 -C.sub.6 alkyl, (iii) 1-
or 2-naphthyl, (iv) 2- or 3-benzofuranyl, (v) 2- or 3-benzothiophenyl,
(vi) 2- or 3-thienyl, (vii) 2-, 3- or 4-pyridyl, (viii) 2- or 3-furanyl,
(ix) 1,3-benzodioxanyl, (x) substituted 1,3-benzodioxanyl, (xi)
quinolinyl, (xii) 2- or 3-indolyl or (xiii) N-substituted 2- or 3-indolyl;
R.sup.1 is C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.4 alkylphenyl, hydrogen,
phenyl or phenyl substituted with one or two substituents independently
selected from Cl, Br, F, I, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4
alkoxy, hydroxy, trifluoromethyl, --NH.sub.2, --NH(C.sub.1 -C.sub.4
alkyl), --N(C.sub.1 -C.sub.4 alkyl).sub.2 or C.sub.1 -C.sub.4 alkylthio;
R.sup.2 and R.sup.3 are each hydrogen or when taken together form a bond;
R.sup.4 and R.sup.5 are each hydrogen or when taken together are .dbd.S, or
when one of R.sup.4 and R.sup.5 is hydrogen, the other is --SCH.sub.3 ;
R.sup.6 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl,
C.sub.2 -C.sub.6 alkenyl, --SO.sub.2 CH.sub.3 or --(CH.sub.2).sub.p --Y
where p is 0, 1, 2, or 3 and Y is cyano OR.sup.8,
##STR10##
tetrazolyl, --NR.sup.10 R.sup.11, --SH, C.sub.1 -C.sub.4 alkylthio or
##STR11##
where R.sup.8 is hydrogen, C.sub.1 -C.sub.4 alkyl, or
##STR12##
R.sup.9 is hydrogen, C.sub.1 -C.sub.4 alkyl or NH.sub.2 ; and R.sup.10
and R.sup.11 are each independently hydrogen, C.sub.1 -C.sub.6 alkyl,
C.sub.2 -C.sub.6 alkenyl, --(CH.sub.2).sub.q OH, --(CH.sub.2).sub.q
N(C.sub.1 -C.sub.4 alkyl).sub.2, --(CH.sub.2).sub.q S(C.sub.1 -C.sub.4
alkyl), C.sub.2 -C.sub.6 alkynyl, phenyl, or C.sub.1 -C.sub.4 alkylphenyl,
where q is 1 to 6, both inclusive, or R.sup.10 and R.sup.11, taken
together with the nitrogen atom to which they are attached, form a
morpholinyl, piperidinyl, piperazinyl or N-methylpiperazinyl ring; and
m is 0, 1, or 2;
with the provisos that
when Ar is (i) phenyl, (ii) phenyl substituted with from one to three
substituents selected from C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8
alkoxy, F, Cl, trifluoromethyl, phenoxy, C.sub.1 -C.sub.4 alkyloxyphenyl,
C.sub.1 -C.sub.8 alkylthio, NO.sub.2, --N(R.sup.7).sub.2 or --COOR.sup.7,
where each R.sup.7 is independently hydrogen or C.sub.1 -C.sub.6 alkyl,
(iii) 1- or 2-naphthyl, (iv) 2- or 3-benzofuranyl, (v) 2- or
3-benzothiophenyl, (vi) 2- or 3-thienyl, (vii) 2- or 3-indolyl, (viii) 2-
or 3-furanyl, (ix) quinolinyl or (x) 2-, 3- or 4-pyridyl; R.sup.1 is
hydrogen or C.sub.1 -C.sub.6 alkyl; R.sup.2 and R.sup.3 taken together
form a bond; m is 0; and R.sup.4 and R.sup.5 taken together are .dbd.S,
R.sup.6 must be other than hydrogen or C.sub.1 -C.sub.6 alkyl;
when Ar is phenyl; R.sup.1 is hydrogen, methyl or ethyl; R.sup.2 and
R.sup.3 taken together form a bond; m is 0; R.sup.4 and R.sup.5 taken
together are .dbd.S; R.sup.6 must be other than phenyl or C.sub.1 -C.sub.4
alkylphenyl;
Ar cannot be phenyl substituted solely with one chloro substituent at the
4-position of the phenyl ring;
when Ar is phenyl substituted with two ethoxy moieties at the 3- and
4-positions of the phenyl ring, R.sup.1 must be hydrogen;
Ar cannot be phenyl substituted with a COOH moiety at the 2-position of the
phenyl ring; and
when R.sup.4 and R.sup.5 are each hydrogen R.sup.6 cannot be C.sub.1
-C.sub.6 alkyl,
and the pharmaceutically acceptable salts thereof.
In addition to the genus of novel compounds described by formula II, above,
certain other of the compounds which can be employed in the methods of the
present invention also appear to be novel. These compounds, while
structurally similar to compounds specifically known in the art (see, for
example, European Patent Application Nos. 343643, 391644 and 39817 as well
as U.S. Pat. No. 4,552,891), are not actually described in any of those
patents or applications. As such, the present invention also encompasses
the following novel compounds and their pharmaceutically acceptable salts:
5-(2-nitrophenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(4-fluorophenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(2-thienyl)methylene!-2-thioxo-4-thiazolidinone;
5-(2-furanyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3,4,5-trimethoxyphenyl)methylmethylene!-2-thioxo-4-thiazolidinone;
4-(2-thioxo-4-thiazolidinone)methylene!benzoic acid;
5-(3-hydroxy-4-nitrophenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3-hydroxyphenyl)methylmethylene!-2-thioxo-4-thiazolidinone;
5-(3-methoxy-4-pentoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3-hydroxy-4-ethoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(4-pentoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3-ethoxy-4-propoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3-propoxy-4-ethoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3,4-dipropoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-3-(methyloxyphenyl)phenyl!methylene!-2-thioxo-4-thiazolidinone;
5-3,5-bis(1,1-dimethylethyl)-4-methoxyphenyl!-methylene!-2-thioxo-4-thiaz
olidinone;
5-(3-ethoxy-4-hydroxy)phenyl!methylene!-2-thioxo-3-methyl-4-thiazolidinone
;
5-(3-ethoxy-4-hydroxyphenyl)methylene!-2-thioxo-3-dimethylamino-4-thiazoli
dinone
5-(3,4-dipentoxyphenyl)methylene!-4-oxo-2-thioxo-3-thiazolidine acetic
acid;
5-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl!methylene!-4-oxo-2-thioxo-3-
thiazolidine acetic acid;
5-(3,5-dichloro-4-hydroxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3-ethoxy-4-butoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3-ethoxy-4-methoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-3,5-bis(1-methylpropyl)-4-hydroxyphenyl!methylene!-4-oxo-2-thioxo-3-thi
azolidine acetic acid;
5-(4-butoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3-methoxy-4-pentoxyphenyl)methylene!-2-thioxo-3-methyl-4-thiazolidinone
;
5-(3-methoxy-4-octoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3,5-dimethoxy-4-pentoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-3-(1,1-dimethylethyl)-4-hydroxy-5-(methyl-thiophenyl)phenyl!methylene!-
2-thioxo-4-thiazolidinone;
5-3-ethoxy-4-hydroxy-5-(methylthiophenyl)phenyl!methylene!-2-thioxo-4-thi
azolidinone;
5-3-ethoxy-4-hydroxy-5-(methylthiophenyl)phenyl!methylene!-2-thioxo-3-met
hyl-4-thiazolidinone;
5-3-ethoxy-4-hydroxy-5-(methylthiophenyl)phenyl!methylene!-4-oxo-2-thioxo
-3-thiazolidine acetic acid;
5-(3-(1,1-dimethylethyl)-4-hydroxyphenyl!methylene!-2-thioxo-3-methyl-4-th
iazolidinone.
Certain of the above compounds and, in particular,
5-(4-pentoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3-propoxy-4-ethoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3-ethoxy-4-butoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(4-butoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3-methoxy-4-pentoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl!methylene!-4-oxo-2-thioxo-3
-thiazolidine acetic acid; and
5-3,5-bis(1-methylpropyl)-4-hydroxy-phenyl!methylene!-4-oxo-2-thioxo-3-t
hiazolidine acetic acid (especially the latter three compounds), appear to
possess a surprising ability to lower blood glucose levels in mammals
compared to structurally similar compounds known in the art. Because of
such surprising activity, these compounds are particularly preferred
compounds of the present invention.
In addition,
5-3-(1,1-dimethylethyl)-4-hydroxy-5-(methylthiophenyl)phenyl!methylene!-
2-thioxo-4-thiazolidinone,
5-(3,5-dichloro-4-hydroxyphenyl)methylene!-2-thioxo-4-thiazolidinone,
5-(3-ethoxy-4-butoxyphenyl)methylene!-2-thioxo-4-thiazolidinone,
5-3-ethoxy-4-hydroxy-5-(methylthiophenyl)phenyl!methylene!-2-thioxo-4-th
iazolidinone,
5-3-ethoxy-4-hydroxy-5-(methylthiophenyl)phenyl!methylene!-4-oxo-2-thiox
o-3-thiazolidine acetic acid,
5-(3-ethoxy-4-hydroxyphenyl)methylene!-2-thioxo-3-methyl-4-thiazolidinone
, 5-(3-ethoxy-4-hydroxyphenyl)methylene!-2-thioxo-3-dimethylamino-4-thiazo
lidinone, 5-(3,4-dipentoxyphenyl)-methylene!-4-oxo-2-thioxo-3-thiazolidine
acetic acid and
5-3-(1,1-dimethylethyl)-4-hydroxyphenyl!methylene-2-thioxo-3-methyl-4-th
iazolidinone appear to possess a surprising ability to inhibit cathepsin D
levels compared to structurally similar compounds known in the art.
Because of such surprising activity, such compounds are also particularly
preferred compounds of the present invention.
Finally, the present invention also provides pharmaceutical formulations
comprising a compound of the present invention, or a pharmaceutically
acceptable salt thereof, in combination with one or more pharmaceutically
acceptable carriers, diluents or excipients therefor.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "C.sub.1 -C.sub.8 alkyl" represents a straight or
branched alkyl chain having from one to eight carbon atoms. Typical
C.sub.1 -C.sub.8 alkyl groups include methyl, ethyl, n-propyl, isopropyl,
n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, and the like. The term
"C.sub.1 -C.sub.8 alkyl" includes within its definition the terms "C.sub.1
-C.sub.4 alkyl" and "C.sub.1 -C.sub.6 alkyl".
"C.sub.1 -C.sub.4 alkylphenyl" represents a straight or branched chain
alkyl group having from one to four carbon atoms attached to a phenyl
ring. Typical C.sub.1 -C.sub.4 alkylphenyl groups include methylphenyl,
ethylphenyl, n-propylphenyl, isopropylphenyl, n-butylphenyl,
isobutylphenyl, and tert-butylphenyl.
The term "C.sub.1 -C.sub.4 alkylthiophenyl" represents a straight or
branched chain alkyl group having from one to four carbon atoms attached
to a thiophenyl moiety. Typical C.sub.1 -C.sub.4 alkylthiophenyl groups
include methylthiophenyl, ethylthiophenyl, isobutylthiophenyl and the
like.
In a similar fashion, the term "C.sub.1 -C.sub.4 alkyloxyphenyl" represents
a straight or branched chain alkyl group having from one to four carbon
atoms attached to phenoxy moiety. Typical C.sub.1 -C.sub.4 alkyloxyphenyl
groups include methyloxyphenyl, ethyloxyphenyl, propyloxyphenyl and the
like.
"C.sub.1 -C.sub.8 alkoxy" represents a straight or branched alkyl chain
having one to eight carbon atoms, which chain is attached to the remainder
of the molecule by an oxygen atom. Typical C.sub.1 -C.sub.8 alkoxy groups
include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
sec-butoxy, tert-butoxy, pentoxy, hexoxy, heptoxy, and the like. The term
"C.sub.1 -C.sub.8 alkoxy" includes within its definition the term "C.sub.1
-C.sub.4 alkoxy".
"C.sub.1 -C.sub.8 alkylthio" represents a straight or branched alkyl chain
having one to eight carbon atoms, which chain is attached to the remainder
of the molecule by a sulfur atom. Typical C.sub.1 -C.sub.8 alkylthio
groups include methylthio, ethylthio, propylthio, butylthio,
tert-butylthio, octylthio and the like. The term "C.sub.1 -C.sub.8
alkylthio" includes within its definition the term "C.sub.1 -C.sub.4
alkylthio".
The term "C.sub.2 -C.sub.6 alkenyl" refers to straight and branched chain
radicals of two to six carbon atoms, both inclusive, having a double bond.
As such, the term includes ethylene, propylene, 1-butene, 2-butene,
2-methyl-1-propene, 1-pentene, 2-methyl-2-butene and the like.
The term "C.sub.2 -C.sub.6 alkynyl" refers to straight and branched chain
radicals of two to six carbon atoms, both inclusive, having a triple bond.
As such, the term includes acetylene, propyne, 1-butyne, 2-hexyne,
1-pentyne, 3-ethyl-1-butyne and the like.
The term "C.sub.3 -C.sub.8 cycloalkyl" refers to saturated alicyclic rings
of three to eight carbon atoms, both inclusive, such as cyclopropyl,
methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the
like.
The terms "1,3-benzodioxanyl" and "substituted 1,3-benzodioxanyl" refer to
structures of the formulae
##STR13##
where each R is independently hydrogen or C.sub.1 -C.sub.4 alkyl.
"Quinolinyl" refers to a quinoline ring system which is attached to the
rest of the molecule at the 4, 5, 6, 7 or 8 position of such ring system.
"N-substituted 2- or 3-indolyl" refers to a 2- or 3-indolyl ring system
substituted on the nitrogen atom of that ring system with a C.sub.1
-C.sub.6 alkyl, C.sub.1 -C.sub.4 alkylphenyl, or C.sub.3 -C.sub.8
cycloalkyl group.
The term "pharmaceutically acceptable salts" refers to salts of the
compounds of the above formulae which are substantially non-toxic to
living organisms. Typical pharmaceutically acceptable salts include those
salts prepared by reaction of the compounds of the above formulae with a
pharmaceutically acceptable mineral or organic acid, or a pharmaceutically
acceptable alkali metal or organic base, depending on the types of
substituents present on the compounds of the formulae.
Examples of pharmaceutically acceptable mineral acids which may be used to
prepare pharmaceutically acceptable salts include hydrochloric acid,
phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid,
phosphorous acid and the like. Examples of pharmaceutically acceptable
organic acids which may be used to prepare pharmaceutically acceptable
salts include aliphatic mono and dicarboxylic acids, oxalic acid, carbonic
acid, citric acid, succinic acid, phenyl-substituted alkanoic acids,
aliphatic and aromatic sulfonic acids and the like. Such pharmaceutically
acceptable salts prepared from mineral or organic acids thus include
hydrochloride, hydrobromide, nitrate, sulfate, pyrosulfate, bisulfate,
sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate,
metaphosphate, pyrophosphate, hydroiodide, hydrofluoride, acetate,
propionate, formate, oxalate, citrate, lactate, p-toluenesulfonate,
methanesulfonate, maleate, and the like.
Many compounds of formulae I, Ia or II which contain a carboxy, carbonyl,
hydroxy or sulfoxide group may be converted to a pharmaceutically
acceptable salt by reaction with a pharmaceutically acceptable alkali
metal or organic base. Examples of pharmaceutically acceptable organic
bases which may be used to prepare pharmaceutically acceptable salts
include ammonia, amines such as triethanolamine, triethylamine,
ethylamine, and the like. Examples of pharmaceutically acceptable alkali
metal bases included compounds of the general formula MOR.sup.13, where M
represents an alkali metal atom, e.g. sodium, potassium, or lithium, and
R.sup.13 represents hydrogen or C.sub.1 -C.sub.4 alkyl.
It should be recognized that the particular anion or cation forming a part
of any salt of this invention is not critical, so long as the salt, as a
whole, is pharmacologically acceptable and as long as the anion or
cationic moiety does not contribute undesired qualities.
A preferred genus of compounds useful in the instantly claimed method of
reducing blood glucose concentrations includes those compounds wherein Ar,
R.sup.1, R.sup.2, R.sup.3, m, R.sup.4, and R.sup.5 are as set forth for
formula I, and R.sup.6 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3
-C.sub.8 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, --SO.sub.2 CH.sub.3 or
--(CH.sub.2).sub.p --Y where p is 0, 1, 2, or 3 and Y is cyano,
--OR.sup.8,
##STR14##
tetrazolyl, NR.sup.10 R.sup.11, --SH, --S(C.sub.1 -C.sub.4 alkyl), or
##STR15##
where R.sup.8 is hydrogen, C.sub.1 -C.sub.4 alkyl, or
##STR16##
R.sup.9 is hydrogen, C.sub.1 -C.sub.4 alkyl, or NH.sub.2 ; and R.sup.10
and R.sup.11 are each independently hydrogen, C.sub.1 -C.sub.6 alkyl,
C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, phenyl, C.sub.1
-C.sub.4 alkylphenyl, --(CH.sub.2).sub.q OH, --(CH.sub.2).sub.q N(C.sub.1
-C.sub.4 alkyl).sub.2, or --(CH.sub.2).sub.q S(C.sub.1 -C.sub.4 alkyl)
where q is 1 to 6, both inclusive, or R.sup.10 and R.sup.11, taken
together with the nitrogen atom to which they are attached, form a
morpholinyl, piperidinyl, piperazinyl, or N-methylpiperazinyl ring.
Of this preferred genus, those compounds in which m is 0 are more
preferred.
Of this more preferred genus, those compounds in which R.sup.4 and R.sup.5
taken together are .dbd.S are even more preferred.
Of this even more preferred genus, those compounds in which R.sup.1 is
hydrogen are especially preferred.
Of this especially preferred genus, those compounds in which R.sup.6 is
hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, or
--(CH.sub.2).sub.p --Y where p is 0, 1, 2, or 3 and Y is --OR.sup.8,
##STR17##
--NR.sup.10 R.sup.11, or C.sub.1 -C.sub.4 alkylthio where R.sup.8 is
hydrogen, C.sub.1 -C.sub.4 alkyl or
##STR18##
R.sup.9 is hydrogen, C.sub.1 -C.sub.4 alkyl or NH.sub.2 ; and R.sup.10 and
R.sup.11 are each independently hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2
-C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, phenyl, or C.sub.1 -C.sub.4
alkylphenyl are particularly preferred.
Of this particularly preferred genus, those compounds in which R.sup.6 is
hydrogen, C.sub.1 -C.sub.6 alkyl, or C.sub.2 -C.sub.6 alkenyl are more
particularly preferred.
of this more particularly preferred genus, those compounds in which Ar is
(i) phenyl, (ii) phenyl substituted with from one to three substituents
independently selected from C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8
alkoxy, C.sub.1 -C.sub.8 alkylthio, trifluoromethyl, C.sub.1 -C.sub.4
alkylphenyl, phenyl, NO.sub.2, F, Cl, hydroxy, phenoxy, C.sub.1 -C.sub.4
alkyloxyphenyl, thiophenyl, C.sub.1 -C.sub.4 alkylthiophenyl,
--COOR.sup.7, --N(R.sup.7)SO.sub.2 R.sup.7 or --N(R.sup.7).sub.2, where
each R.sup.7 is independently hydrogen or C.sub.1 -C.sub.6 alkyl, (iii)
2-, 3- or 4-pyridyl, or (iv) 2- or 3-furanyl are substantially preferred.
Of this substantially preferred genus, those compounds wherein Ar is phenyl
substituted with from one to three substituents independently selected
from C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.4
alkylphenyl, phenyl, NO.sub.2, F, Cl, hydroxy, phenoxy, C.sub.1 -C.sub.4
alkylthiophenyl, --COOR.sup.7 or --N(R.sup.7)SO.sub.2 R.sup.7, where each
R.sup.7 is independently hydrogen or C.sub.1 -C.sub.6 alkyl, are more
substantially preferred.
Of this more substantially preferred genus, those compounds wherein Ar is
phenyl substituted with from one to three substituents independently
selected from C.sub.1 -C.sub.8 alkyl (especially C.sub.1 -C.sub.4 alkyl),
C.sub.1 -C.sub.8 alkoxy (especially C.sub.1 -C.sub.6 alkoxy), or hydroxy
are even more substantially preferred.
The most preferred compounds which may be employed in the method of
reducing blood glucose concentrations of the present invention include
5-(3,4-diethoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3-methoxy-4-butoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3-methoxy-4-pentoxy-phenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3-methoxy-4-pentoxyphenyl)methylene!-2-thioxo-4-thiazolidinone, sodium
salt; 5-(3-methoxy-4-pentoxyphenyl)methyl!-2-thioxo-4-thiazolidinone;
53,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl!methylene!-2-thioxo-4-thiazo
lidinone;
5(3,5-dimethyl-4-hydroxyphenyl)methylene!-2-thioxo-4-thiazolidinone and
5-(3,5-dimethoxy-4-hydroxyphenyl)methylene!-2-thioxo-4-thiazolidinone.
A preferred genus of compounds useful in the instantly claimed method of
treating Alzheimer's disease includes those compounds wherein Ar, R.sup.1,
R.sup.2, R.sup.3, m, R.sup.4 and R.sup.5 are as set forth for formula Ia,
and R.sup.6 is hydrogen, C.sub.1 -C.sub.6 alkyl or --(CH.sub.2).sub.p Y
where p is 0, 1, 2 or 3 and Y is
##STR19##
where R.sup.9 is hydrogen, C.sub.1 -C.sub.4 alkoxy or hydroxy, or
--NR.sup.10 R.sup.11 where R.sup.10 and R.sup.11 are each independently
hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl or C.sub.1 -C.sub.4 alkylphenyl.
Of this preferred genus, those compounds in which m is 0 are more
preferred.
Of this more preferred genus, those compounds in which R.sup.4 and R.sup.5
taken together are .dbd.S are even more preferred.
Of this even more preferred genus, those compounds in which R.sup.2 and
R.sup.3 taken together form a bond are especially preferred.
Of this especially preferred genus, those compounds in which Ar is phenyl
substituted with from one to three substituents independently selected
from C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8
alkylthio, trifluoromethyl, C.sub.1 -C.sub.4 alkylphenyl, phenyl,
NO.sub.2, F, Cl, hydroxy, phenoxy, C.sub.1 -C.sub.4 alkyloxyphenyl,
thiophenyl, C.sub.1 -C.sub.4 alkylthiophenyl, --COOR.sup.7,
--N(R.sup.7)SO.sub.2 R.sup.7 or --N(R.sup.7).sub.2, where each R.sup.7 is
independently hydrogen or C.sub.1 -C.sub.4 alkyl, are particularly
preferred.
Of this particularly preferred genus, those compounds in which R.sup.1 is
hydrogen are more particularly preferred.
Of this more particularly preferred genus, those compounds in which Ar is
phenyl substituted with from one to three substituents independently
selected from phenoxy, phenyl, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8
alkyl (especially C.sub.1 -C.sub.4 alkyl), hydroxy, Cl, F, C.sub.1
-C.sub.4 alkylthiophenyl, C.sub.1 -C.sub.4 alkyloxyphenyl,
--N(R.sup.7)SO.sub.2 R.sup.7 and --N(R.sup.7).sub.2, where each R.sup.7 is
independently hydrogen or C.sub.1 -C.sub.4 alkyl, are substantially
preferred.
The most preferred compounds which may be employed in the method of
treating Alzheimer's disease of the present invention include
5-(4-phenoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3-phenoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(1,1'-biphenyl)-4-yl!methylene!-2-thioxo-4-thiazolidinone;
5-(3-methoxy-4-hexoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3-methoxy-4-heptoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3-methoxy-4-octoxyphenyl!methylene!-2-thioxo-4-thiazolidinone;
5-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl!methylene!-2-thioxo-4-thiaz
olidinone;
5-(3,5-dichloro-4-hydroxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-3-(1,1-dimethylethyl)-4-hydroxy-5-(methylthiophenyl)phenyl!methylene!-
2-thioxo-4-thiazolidinone;
5-(3-methoxy-4-heptoxyphenyl)methylene!-2-thioxo-3-dimethylamino-4-thiazo
lidinone;
5-(3-ethoxy-4-hydroxyphenyl)methylene!-2-thioxo-4-thiazolidinone; 5-(3-e
thoxy-4-butoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-3-ethoxy-4-hydroxy-5-(methylthiophenyl)phenyl!methylene!-2-thioxo-4-th
iazolidinone;
5-3-ethoxy-4-hydroxy-5-(methylthiophenyl)phenyl!methylene!-4-oxo-2-thiox
o-3-thiazolidine acetic acid;
5-3-(methyloxy-phenyl)phenyl!methylene!-2-thioxo-4-thiazolidinone;
5-(3-ethoxy-4-hydroxyphenyl)methylene!-2-thioxo-3-methyl-4-thiazolidinone
; 5-(3-ethoxy-4-hydroxyphenyl)methylene!-2-thioxo-3-dimethylamino-4-thiazo
lidinone; 5-(3,4-dipentoxyphenyl)methylene!-4-oxo-2-thioxo-3-thiazolidine
acetic acid;
5-3-(1,1-dimethylethyl)-4-hydroxyphenyl!methylene!-2-thioxo-3-methyl-4-t
hiazolidinone; and
5-4-(dimethylamino)phenyl!methylene!-2-thioxo-4-thiazolidinone.
A preferred genus of compounds of the present invention includes those
compounds wherein Ar, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 are as set forth for Formula II, and m is 0. Of this preferred
genus, those compounds in which R.sup.4 and R.sup.5 taken together are
.dbd.S are more preferred. Of this more preferred genus, those compounds
in which R.sup.2 and R.sup.3 taken together form a bond are especially
preferred.
Of this especially preferred genus, those compounds in which R.sup.6 is
hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, or
--(CH.sub.2).sub.p --Y where p is 0, 1, 2, or 3 and Y is --OR.sup.8,
##STR20##
--NR.sup.10 R.sup.11, or C.sub.1 -C.sub.4 alkylthio, where R.sup.8 is
hydrogen, C.sub.1 -C.sub.4 alkyl or
##STR21##
R.sup.9 is hydrogen, C.sub.1 -C.sub.4 alkyl or NH.sub.2 ; and R.sup.10 and
R.sup.11 are each independently hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2
-C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, phenyl, or C.sub.1 -C.sub.4
alkylphenyl are particularly preferred.
Of this particularly preferred genus, those compounds in which R.sup.6 is
hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl or --NR.sup.10
R.sup.11 where R.sup.10 and R.sup.11 are independently C.sub.1 -C.sub.6
alkyl are more particularly preferred. Of this more particularly preferred
genus, those compounds in which R.sup.1 is hydrogen or phenyl are even
more particularly preferred.
Of this even more particularly preferred genus, those compounds in which Ar
is (i) phenyl, (ii) phenyl substituted with from one to three substituents
independently selected from C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8
alkoxy, C.sub.1 -C.sub.8 alkylthio, trifluoromethyl, C.sub.2 -C.sub.4
alkylphenyl, NO.sub.2, F, Cl, phenoxy, C.sub.1 -C.sub.4 alkoxyphenyl,
thiophenyl, C.sub.1 -C.sub.4 alkylthiophenyl, --COOR.sup.7,
--N(R.sup.7)SO.sub.2 R.sup.7 or --N(R.sup.7).sub.2, where each R.sup.7 is
independently hydrogen or C.sub.1 -C.sub.6 alkyl, (iii)
1,3-benzodioxanyl,(iv) substituted 1,3-benzodioxanyl or (v) quinolinyl are
substantially preferred compounds.
Of this substantially preferred genus, those compounds wherein Ar is (i)
phenyl substituted with from one to three of phenoxy, C.sub.1 -C.sub.8
alkoxy, C.sub.1 -C.sub.4 alkyloxyphenyl or --N(R.sup.7)SO.sub.2 R.sup.7,
where each R.sup.7 is hydrogen or C.sub.1 -C.sub.6 alkyl or (ii)
1,3-benzodioxanyl are more substantially preferred.
Certain preferred compounds of the present invention include
5-(diphenylmethylene)-2-thioxo-4-thiazolidinone;
5-(1,3-benzodioxol-5-yl)methylene)-2-thioxo-4-thiazolidinone;
5-(4-phenoxyphenyl)methylene!-2-thioxo-4-thiazolidinone;
5-(3-methoxy-4-heptoxyphenyl)methylene!-3-amino-2-thioxo-4-thiazolidinone
; 5-(3-methoxy-4-heptoxyphenyl)methylene!-3-dimethylamino-2-thioxo-4-thiaz
olidinone;
5-(3,4-diheptoxyphenyl)methylene!-2-thioxo-3-dimethylamino-4-thiazolidino
ne;
5-(3,4-dibutoxyphenyl)methylene!-2-thioxo-3-dimethylamino-4-thiazolidinon
e;
5-(3-methoxy-4-heptoxyphenyl)methylene!-2-thioxo-3-(2-propenyl)-4-thiazol
idinone;
5-(3-methanesulfonamidophenyl)methylene!-4-oxo-2-thioxo-3-thiazolidine
acetic acid;
5-3-(methyloxyphenyl)phenyl!methylene!-2-thioxo-4-thiazolidinone;
5-(3-methoxy-4-heptoxyphenyl)methylene!-2-thioxo-3-dimethylamino-4-thiazo
lidinone; and
5-(3-methanesulfonamidophenyl)methylene!-2-thioxo-4-thiazolidinone.
An alternative preferred genus of compounds of the present invention
includes those compounds wherein Ar, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, and m are as defined for formula II, and R.sup.6 is C.sub.3
-C.sub.8 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, --SO.sub.2 CH.sub.3 or
--(CH.sub.2).sub.p --Y where p is 0, 1, 2, or 3 and Y is cyano,
--OR.sup.8,
##STR22##
tetrazolyl, --NR.sup.10 R.sup.11, --SH, C.sub.1 -C.sub.4 alkylthio, or
##STR23##
where R.sup.8 is hydrogen, C.sub.1 -C.sub.4 alkyl, or
##STR24##
R.sup.9 is hydrogen, C.sub.1 -C.sub.4 alkyl, or NH.sub.2 ; and R.sup.10
and R.sup.11 are each independently hydrogen, C.sub.1 -C.sub.6 alkyl,
C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, phenyl, C.sub.1
-C.sub.4 alkylphenyl, --(CH.sub.2).sub.q OH, --(CH.sub.2).sub.q N(C.sub.1
-C.sub.4 alkyl).sub.2, or --(CH.sub.2).sub.q S(C.sub.1 -C.sub.4 alkyl)
where q is 1 to 6, both inclusive, or R.sup.10 and R.sup.11, taken
together with the nitrogen atom to which they are attached, form a
morpholinyl, piperidinyl, piperazinyl, or N-methylpiperazinyl ring.
Of this preferred genus, those compounds in which m is 0 are more
preferred.
Of this more preferred genus, those compounds in which R.sup.4 and R.sup.5
taken together are .dbd.S are even more preferred.
Of this even more preferred genus, those compounds in which R.sup.2 and
R.sup.3 taken together form a bond are especially preferred
Of this especially preferred genus, those compounds in which R.sup.6 is
C.sub.2 -C.sub.6 alkenyl, or --(CH.sub.2).sub.p --Y where p is 0, 1, 2, or
3 and Y is --OR.sup.8,
##STR25##
--NR.sup.10 R.sup.11, or C.sub.1 -C.sub.4 alkylthio, where R.sup.8 is
hydrogen, C.sub.1 -C.sub.4 alkyl or
##STR26##
R.sup.9 is hydrogen, C.sub.1 -C.sub.4 alkyl or NH.sub.2 ; and R.sup.10 and
R.sup.11 are each independently hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2
-C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, phenyl, or C.sub.1 -C.sub.4
alkylphenyl are particularly preferred.
Of this particularly preferred genus, those compounds wherein R.sup.1 is
hydrogen or phenyl are more particularly preferred.
Of this more particularly preferred genus, those compounds in which Ar is
(i) phenyl, (ii) phenyl substituted with from one to three substituents
independently selected from C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8
alkoxy, C.sub.1 -C.sub.8 alkylthio, trifluoromethyl, C.sub.2 -C.sub.4
alkylphenyl, NO.sub.2, F, Cl, phenoxy, C.sub.1 -C.sub.4 alkoxyphenyl,
thiophenyl, C.sub.1 -C.sub.4 alkylthiophenyl, --COOR.sup.7,
--N(R.sup.7)SO.sub.2 R.sup.7 or --N(R.sup.7).sub.2, where each R.sup.7 is
independently hydrogen or C.sub.1 -C.sub.6 alkyl (iii) 2-, 3- or
4-pyridyl, or (iv) 2- or 3-furanyl are even more particularly preferred.
Of this even more particularly preferred genus, those compounds wherein Ar
is phenyl substituted with from one to three substituents independently
selected from C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8 alkoxy, C.sub.1
-C.sub.8 alkylthio, trifluoromethyl, C.sub.2 -C.sub.4 alkylphenyl,
NO.sub.2, F, Cl, phenoxy, C.sub.1 -C.sub.4 alkoxyphenyl, thiophenyl,
C.sub.1 -C.sub.4 alkylthiophenyl, --COOR.sup.7, --N(R.sup.7)SO.sub.2
R.sup.7 or --N(R.sup.7).sub.2, where each R.sup.7 is independently
hydrogen or C.sub.1 -C.sub.6 alkyl, are substantially preferred.
Of this substantially preferred genus, those compounds wherein Ar is phenyl
substituted with from one to three substituents independently selected
from C.sub.1 -C.sub.8 alkyl or C.sub.1 -C.sub.8 alkoxy are most preferred.
The present invention also encompasses formulations comprising a compound
of the present invention in combination with a pharmaceutically acceptable
carrier, diluent, or excipient therefor. Preferred formulations of the
present invention are those formulations which contain a preferred
compound or genus of compounds of the present invention, as described
above.
The compounds of the present invention, as well as the compounds employed
in the methods of the present invention, can, typically, be prepared by
methods well known to one skilled in the art of organic chemistry. For
example, such compounds may be prepared by condensation of rhodanine, or
an appropriately substituted rhodanine derivative, with an appropriately
substituted aromatic aldehyde or aldehyde derivative such as a mono or
disubstituted imine of the formula
##STR27##
Such reaction is illustrated utilizing an appropriately substituted
aromatic aldehyde as follows
##STR28##
where Ar and R.sup.6 are as defined in formulae I, Ia and II.
Compounds of the present invention (as well as those compounds employed in
the methods of the present invention) wherein R.sup.2 and R.sup.3 are
hydrogen, or when taken together form a bond, and R.sup.4 and R.sup.5 are
each hydrogen can be prepared by subjecting the compound wherein R.sup.4
and R.sup.5 taken together form .dbd.S to catalytic hydrogenation. The
relative proportions of compound obtained (R.sup.2, R.sup.3, R.sup.4 and
R.sup.5 all hydrogen vs. R.sup.2 and R.sup.3 taken together form a bond
and R.sup.4 and R.sup.5 are hydrogen) depends upon the temperature,
pressure, and duration of hydrogenation, the solvent employed and the
particular catalyst used. Alternatively, the above transformations may be
accomplished by heating the compounds wherein R.sup.4 and R.sup.5 taken
together are .dbd.S and R.sup.2 and R.sup.3 taken together are a double
bond in a mixture of hydrochloric acid and an alcohol, such as ethanol, in
the presence of zinc. Reduction of the thione without affecting the
benzylic double bond may be accomplished by heating the thione with a
reducing agent such as tri-n-butyl tin hydride in a non-reactive solvent,
such as toluene, and preferably in the presence of a free radical
initiator, such as azobisisobutyronitrile. However, for such reduction to
work, an N-substituted rhodanine substrate must be employed.
The transformation of compounds wherein R.sup.2 and R.sup.3 taken together
form a bond and R.sup.4 and R.sup.5 taken together are .dbd.S to those
compounds wherein R.sup.2 and R.sup.3 are both hydrogen while R.sup.4 and
R.sup.5 remain unchanged may be accomplished by treating the unsaturated
compound with a dihydropyridine, such as diethyl
2,6-dimethyl-1,4-dihydro-3,5-pyridine dicarboxylate in the presence of
silica gel. The reaction is best carried out in the presence of a
nonreactive solvent such as benzene or toluene, preferably under an inert
atmosphere. The reaction may be accomplished at temperatures from about
25.degree. C. up to the reflux temperature of the mixture. At the
preferred temperature of approximately 80.degree. C., the reaction is
essentially complete after about 12-18 hours.
Compounds of formulae I, Ia or II wherein R.sup.1 is C.sub.1 -C.sub.6
alkyl, phenyl, a substituted phenyl of the type described above, or
C.sub.1 -C.sub.4 alkylphenyl may be prepared by conventional
Friedel-Crafts acylation of an appropriately substituted aromatic compound
with an acyl halide of the formula R.sup.1 --C(O)--X, wherein R.sup.1 is
as defined in formulae I or II and X is chloro, fluoro, bromo or iodo. The
resulting aromatic ketone is then condensed with rhodanine, or an
appropriately substituted rhodanine derivative.
The compounds of the present invention (as well as the compounds employed
in the methods of the present invention) allow various R.sup.6
substituents. These R.sup.6 substituents can be prepared as follows.
Compounds of formulae I, Ia and II wherein R.sup.6 is hydrogen, C.sub.1
-C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl or --(CH.sub.2).sub.p --Y
where p is as defined for formulae I, Ia and II and Y is cyano, or
NR.sup.10 R.sup.11 where R.sup.10 and R.sup.11 are each independently
hydrogen or C.sub.1 -C.sub.6 alkyl may be prepared using the method set
forth in the above reaction scheme. Alternatively, rhodanine may be used
for condensation with an aldehyde or aldehyde derivative forming those
species wherein R.sup.6 is hydrogen, followed by alkylation or acylation
with the appropriate R.sup.6 -containing halide. The alkylation or
acylation is usually accomplished in an inert solvent such as
tetrahydrofuran or dimethylformamide and in the presence of a strong base
such as sodium hydride.
Alternatively, compounds of formulae I, Ia and II wherein R.sup.6 is
--(CH.sub.2).sub.p --Y where Y is cyano may be prepared by treating the
non-cyanated analog with a halo-substituted aliphatic nitrile. From this
cyano derivative the tetrazolyl is prepared as by treatment with
tri-N-butyl tin azide in, for example, ethylene glycol dimethyl ether.
Compounds of formulae I, Ia and II wherein R.sup.6 is --(CH.sub.2).sub.p
--Y (p=0) and Y is NR.sup.10 R.sup.11, where R.sup.10 and R.sup.11 are as
defined in formulae I, Ia and II, may also be prepared by employing an
appropriately substituted hydrazine. In this reaction sequence,
benzaldehyde is reacted with an appropriately substituted hydrazine, in an
alcoholic solvent, yielding III. An appropriately substituted alkyl halide
is then reacted with III, in the presence of triethylamine and
acetonitrile, to provide IV, which is then further reacted with hydrazine
to yield the R.sup.10, R.sup.11 hydrazine V. Compound V may alternatively
be prepared by the reduction of a nitroso-R.sup.10 R.sup.11 amine using
zinc dust and acetic acid or aluminum and a strong base. The R.sup.10,
R.sup.11 hydrazine is then treated with carbon disulfide, chloroacetic
acid and triethylamine to provide intermediate VI. Condensation of VI with
an appropriately substituted aromatic aldehyde or aldehyde derivative
yields the desired product, as represented by the following reaction
scheme.
##STR29##
Furthermore, the thione portion of the compound produced above may be
reduced by treatment with a reducing agent such as tri-n-butyltin hydride
in an inert solvent such as toluene, preferably in the presence of a free
radical initiator such as azobisisobutyronitrile. Preparation of compounds
wherein one of R.sup.10 and R.sup.11 is hydrogen may be effected before or
after reduction of the thione, as desired, by heating the disubstituted
compound in a mixture of ethanol/water in the presence of a catalyst such
as a rhodium catalyst.
Compounds of formulae I, Ia and II wherein R.sup.6 is --(CH.sub.2).sub.p
--Y and Y is OR.sup.8 or NR.sup.10 R.sup.11 (where R.sup.8 is hydrogen,
acetyl or tosyl and R.sup.10 and R.sup.11 are each independently hydrogen
or C.sub.1 -C.sub.6 alkyl) may also be prepared according to the following
reaction scheme:
##STR30##
A hydroxyalkyl rhodanine is prepared by condensing carbon disulfide,
chloroacetic acid, and the appropriate hydroxyalkylamine by standard
techniques. When condensed with the appropriately substituted aromatic
aldehyde (or aldehyde derivative), as described above, the resulting
product is the condensed 2-thioxo-4-thiazolidinone VIII which has been
transformed into the acetyl derivative. The thioxo compound VIII may
optionally be converted to the methylene compound of formulae I or II as
described above. The acetyl group of intermediate IX may be removed upon
treatment with aqueous ammonia in a solvent such as acetonitrile to
provide compound X. The hydroxy compound X is then converted to the tosyl
derivative upon treatment with p-toluenesulfonyl chloride in pyridine,
preferably at temperatures of around 0.degree. C. The versatile tosyl
intermediate XI may then be transformed into the compounds of formulae I
or II upon treatment with an appropriate HNR.sup.10 R.sup.11 amine. This
latter transformation is best accomplished by allowing XI to react in the
presence of a molar excess of the amine. Once again, a solvent such as
acetonitrile is useful for accomplishing this transformation.
Those compounds where m is 1 or 2 are readily prepared from the sulfide
(m=0) by treatment with an oxidizing agent, such as m-chloroperbenzoic
acid, in a suitable solvent for a time sufficient to generate the desired
oxidative state.
Depending upon the definitions of R.sup.1, R.sup.2, and R.sup.3, the
compounds of formulae I, Ia and II may exist in various isomeric forms.
The compounds, formulations and methods of the present invention are not
related to any particular isomer but include all possible isomers and
racemates.
It will be readily appreciated by one skilled in the art that the aromatic
portion of the compounds of the invention (or the compounds employed in
the methods of the present invention) can be provided by compounds which
are either commercially available or may be readily prepared by known
techniques from commercially available starting materials. Similarly, the
rhodanine or N-substituted rhodanine starting material is either
commercially available or may be prepared by well known methods from
commercially available substrates.
The following Examples illustrate the preparation of the compounds of the
present invention, as well as compounds which may be employed in the
methods of the present invention. The Examples are illustrative only and
are not intended to limit the scope of the instant invention in any way.
EXAMPLE 1
5-(3-methanesulfonamidophenyl)methylene!-2-thioxo-4-thiazolidinone
Thirty seven grams (185.9 mmol) of 3-methanesulfonamidbenzaldehyde, 25.0 g
(187.9 mmol) of rhodanine, 48.0 g (585.3 mmol) of anhydrous sodium acetate
and 950 ml of acetic acid were stirred while heating at reflux for 20
hours. The reaction was then stirred at room temperature for approximately
another 60 hours. The resulting slurry was poured into 3000 ml of a 1:1
ethanol/water mixture. Solids precipitated and were recovered by
filtration, washed with water and then vacuum dried to provide 54 g of
title compound. m.p. 260.degree.-265.degree. C.
Analysis for C.sub.11 H.sub.10 N.sub.2 O.sub.3 S.sub.3 Calculated: C,
42.02; H, 3.20; N 8.91; Found: C, 42.15; H, 3.57; N 8.71.
EXAMPLE 2
5-(1,3-benzodioxol-5-yl)methylene!-2-thioxo-4-thiazolidinone
Twenty grams (133.2 mmol) of piperonal were reacted with 17.74 g (133.2
mmol)of rhodanine in 38.24 g (466.2 mmol) of glacial acetic acid at reflux
for about 3 hours. The mixture was then poured into water and stirred
overnight. A precipitate formed which was recovered by filtration and then
air dried overnight to provide 27.8 g of title product. m.p.
194.degree.-195.degree. C.
Analysis for C.sub.11 H.sub.7 N.sub.1 O.sub.3 S.sub.2 : Calculated: C,
49.80; H, 2.66; N 5.28; S, 24.17; Found: C, 50.04; H, 2.38; N 5.27; S,
23.98.
EXAMPLE 3
5-(4-quinolinyl)methylene!-2-thioxo-4-thiazolidinone
Rhodanine (2.2 g; 16.5 mmol), 1.3 ml of concentrated ammonium hydroxide and
1 g of ammonium chloride in 20 ml of ethanol were heated on a steam bath
for 15 minutes. 4-Quinoline carboxaldehyde (2.6 g; 16.5 mmol) was added
and the resulting mixture was heated on the steam bath for another hour.
Upon cooling to 5.degree. C. a precipitate formed. This precipitate was
recovered by filtration and then washed with water to provide 4 g of title
compound, m.p. 325.degree.-328.degree. C.
Analysis for C.sub.13 H.sub.8 N.sub.2 OS.sub.2 : Calculated: C, 57.33; H,
2.96; N 10.29; Found: C, 57.11; H, 3.11; N 10.21.
EXAMPLE 4
5-(diphenylmethylene)-2-thioxo-4-thiazolidinone
One hundred and ninety grams (1.05 mol) of diphenyl kerimine, 140 grams
(1.05 mol) of rhodanine, 5 ml of acetic acid and 1500 ml of toluene were
heated at reflux for 3 hours. Crystals formed upon cooling. The solvent
was decanted, fresh toluene was added to the residue and the resulting
suspension was filtered. The recovered crystals were recrystallized from
methanol to provide 172.0 g of title product, m.p. 192.degree.-194.degree.
C.
Analysis for C.sub.16 H.sub.11 NOS.sub.2 : Calculated: C, 64.62; H, 3.73;
O, 5.38; N 4.71; S, 21.56; Found: C, 64.13; H, 3.84; 0, 5.57; N 4.59; S,
22.38.
EXAMPLE 5
5-(4-phenoxyphenyl)methylene!-2-thioxo-4-thiazolidinone
A mixture of 9.9 g (50.0 mmol) of 4-phenoxybenzaldehyde, 6.8 g (51.1 mmol)
of rhodanine, 15.5 g of sodium acetate and 60 ml of acetic acid was heated
on a steam bath for two hours. The reaction solution was then poured into
water causing crude product to precipitate. The precipitate was filtered
and then washed successively with water followed by diethyl ether to
provide 8.6 g of title product, m.p. 195.degree.-200.degree. C.
Analysis for C.sub.16 H.sub.11 NO.sub.2 S.sub.2 : Calculated: C, 61.32; H,
3.54; N 4.47; Found: C, 61.07; H, 3.63; N 4.47.
The following compounds were synthesized using methods substantially
equivalent to those described in Examples 1-5 above or as described
elsewhere herein.
EXAMPLE 6
5-(phenylmethylene)-2-thioxo-4-thiazolidinone, m.p.
202.degree.-203.5.degree. C.
EXAMPLE 7
5- (2-hydroxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
220.degree.-222.degree. C.
EXAMPLE 8
5-(4-hydroxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
287.degree.-290.degree. C.
EXAMPLE 9
5-(2-nitrophenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
197.5.degree.-199.degree. C.
EXAMPLE 10
5-(3-nitrophenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
277.degree.-280.degree. C.
EXAMPLE 11
5-(3-hydroxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p
242.degree.-244.degree. C.
EXAMPLE 12
5-(2,4-dimethoxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p
253.degree.-255.degree. C.
EXAMPLE 13
5-(4-fluorophenyl)methylene!-2-thioxo-4-thiazolidlnone, m.p
225.degree.-227.degree. C.
EXAMPLE 14
5-(2-thienyl)methylene!-2-thioxo-4-thiazolidinone, m.p
231.degree.-233.degree. C.
EXAMPLE 15
5-(2-furanyl)methylene!-2-thioxo-4-thiazolidinone, m.p
217.degree.-219.degree. C.
EXAMPLE 16
5-(4-pyridyl)methylene!-2-thioxo-4-thiazolidinone, m.p
297.degree.-298.degree. C.
EXAMPLE 17
5-(3,4,5-trimethoxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
203.degree.-205.degree. C.
EXAMPLE 18
5-(4-methoxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
252.degree.-254.degree. C.
EXAMPLE 19
5-(3,4,5-trimethoxyphenyl)methylmethylene!-2-thioxo-4-thiazolidinone, m.p.
210.degree.-213.degree. C.
EXAMPLE 20
5-(3-methoxy-4-hydroxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
229.degree.-231.degree. C.
EXAMPLE 21
5-(4-methoxyphenyl)phenylmethylene!-2-thioxo-4-thiazolidinone, m.p.
169.degree.-171.degree. C.
EXAMPLE 22
5-(3-pyridyl)methylene!-2-thioxo-4-thiazolidinone, m.p. .about.286.degree.
C.
EXAMPLE 23
5-(3-chlorophenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
233.degree.-235.degree. C.
EXAMPLE 24
5-(2,3-dimethoxyphenyl)methylene!-2-thioxo-4-thiazolidinone
EXAMPLE 25
5-(3-methoxyphenyl)methylene!-2-thioxo-4-thiazolidinone
EXAMPLE 26
5-(2-methoxyphenyl)methylene!-2-thioxo-4-thiazolidinone
EXAMPLE 27
5-(3-methyl-4-methoxyphenyl)methylene!-2-thioxo-4-thiazolidinone
EXAMPLE 28
5-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl!methylene!-2-thioxo-4-thiazo
lidinone, m.p. .about.260.degree. C.
EXAMPLE 29
5-(1,1'-biphenyl)-2-yl!methylene!-2-thioxo-4-thiazolidinone
EXAMPLE 30
5-(3-methoxy-4-hydroxyphenyl)methylene!-3-(2-propenyl)-2-thioxo-4-thiazoli
dinone, m.p. 146.degree.-148.degree. C.
EXAMPLE 31
5-(3-methoxy-4-heptoxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
130.degree.-132.degree. C.
EXAMPLE 32
5-(3-ethoxy-4-hydroxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
217.degree.-217.5.degree. C.
EXAMPLE 33
5-(3-methylphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
197.degree.-202.degree. C.
EXAMPLE 34
5-(4-methylphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
229.degree.-234.degree. C.
EXAMPLE 35
5-(2-naphthalenyl)methylene)-2-thioxo-4-thiazolidinone, m.p.
224.degree.-225.degree. C.
EXAMPLE 36
5-(3,4-dichlorophenyl)methylene!-2-thioxo-4-thiazolidinone
EXAMPLE 37
4-(2-thioxo-4-thiazolidinone)methylene!benzoic acid, m.p.
.about.320.degree. C.
EXAMPLE 38
5-(3,4-diethoxyphenyl)methylene!-2-thioxo-4-thiazolidinone
EXAMPLE 39
5-(1H-indol-3-yl)methylene!-2-thioxo-4-thiazolidinone
EXAMPLE 40
5-(3-hydroxy-4-methoxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
218.degree.-220.degree. C.
EXAMPLE 41
5-(3-methoxy-4-butoxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
175.degree.-176.degree. C.
EXAMPLE 42
5-(1,1'-biphenyl)-4-yl!methylene!-2-thioxo-4-thiazolidinone, m.p.
245.degree.-250.degree. C.
EXAMPLE 43
5-(3-hydroxy-4-nitrophenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
.about.224.degree. C.
EXAMPLE 44
5-(3-hydroxyphenyl)methylmethylene!-2-thioxo-4-thiazolidinone
EXAMPLE 45
5-(3-methoxy-4-pentoxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
170.degree.-171.degree. C.
EXAMPLE 46
5-(3-hydroxy-4-ethoxyphenyl)methylene!-2-thioxo-4-thiazolidinone,
m.p.>225.degree. C.
EXAMPLE 47
5-(4-pentoxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
158.5.degree.-160.degree. C.
EXAMPLE 48
5-(3-methoxy-4-ethoxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
207.degree.-207.5.degree. C.
EXAMPLE 49
5-(3-ethoxy-4-propoxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
156.degree.-157.degree. C.
EXAMPLE 50
5-(3-propoxy-4-ethoxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
186.5.degree.-188.degree. C.
EXAMPLE 51
5-(3,4-dipropoxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
167.5.degree.-168.5.degree. C.
EXAMPLE 52
5-(3-methoxy-4-butoxyphenyl)methylene!-2-thioxo-4-thiazolidinone, sodium
salt m.p.>225.degree. C.
EXAMPLE 53
5-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl!methylene!-4-oxo-2-thioxo-3-
thiazolidine acetic acid, m.p. .about.265.degree. C.
EXAMPLE 54
5-(3-methoxy-4-butoxyphenyl)methyl!-2-thioxo-4-thiazolidinone, m.p.
152.degree.-153.5.degree. C.
EXAMPLE 55
5-(3,5-dichloro-4-hydroxyphenyl)methylene!-2-thioxo-4-thiazolidinone,
m.p.>260.degree. C.
EXAMPLE 56
5-(3-ethoxy-4-butoxyphenyl)methylene!-2-thioxo-4-thiazolidinone
EXAMPLE 57
5-(3-methoxy-4-pentoxyphenyl)methylene!-2-thioxo-4-thiazolidinone sodium
salt, m.p. .about.254.degree. C.
EXAMPLE 58
5-(3-ethoxy-4-methoxyphenyl)methylene!-2-thioxo-4-thiazolidinone,
m.p.>225.degree. C.
EXAMPLE 59
5-3,5-bis(1-methylpropyl)-4-hydroxyphenyl!methylene!-4-oxo-2-thioxo-3-thi
azolidine acetic acid, m.p. 191.degree.-193.degree. C.
EXAMPLE 60
5-(3,4-dimethoxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
231.5.degree.-233.degree. C.
EXAMPLE 61
5-(4-propoxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p. 180.degree.
C.
EXAMPLE 62
5-(3,5-dimethyl-4-hydroxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
260.degree. C.
EXAMPLE 63
5-(3,5-dimethoxy-4-hydroxyphenyl)methylene!-2-thioxo-4-thiazolidinone,
m.p. 230.degree. C.
EXAMPLE 64
5-(3-methoxy-4-pentoxyphenyl)methyl!-2-thioxo-4-thiazolidinone, m.p.
163.degree.-164.degree. C.
EXAMPLE 65
5-(3-methoxy-4-pentoxyphenyl)methylene!-2-thioxo-3-methyl-4-thiazolidinone
, m.p. 117.degree.-118.degree. C.
EXAMPLE 66
5-(3-methoxy-4-pentoxyphenyl)methylene!-4-thiazolidinone, m.p.
174.degree.-175.degree. C.
EXAMPLE 67
5-(3-methoxy-4-pentoxyphenyl)methyl!-4-thiazolidinone, m.p.
108.degree.-109.degree. C.
EXAMPLE 68
5-(3-methoxy-4-hexoxyphenyl)methylene!-2-thioxo-4-thiazolidinone
EXAMPLE 69
5-(3-methoxy-4-octoxyphenyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
125.degree.-127.degree. C.
EXAMPLE 70
5-(3,5-dimethoxy-4-pentoxyphenyl)methylene!-2-thioxo-4-thiazolidinone,
m.p. 166.degree.-167.degree. C.
EXAMPLE 71
5-3-(1,1-dimethylethyl)-4-hydroxy-5-(methylthiophenyl)phenyl!methylene!-2
-thioxo-4-thiazolidinone, m.p. 181.degree.-184.degree. C.
EXAMPLE 72
5-3-ethoxy-4-hydroxy-5-(methylthiophenyl)phenyl!methylene!-2-thioxo-4-thi
azolidinone, m.p. 190.degree.-192.degree. C.
EXAMPLE 73
5-3-ethoxy-4-hydroxy-5-(methylthiophenyl)phenyl!methylene!-2-thioxo-3-met
hyl-4-thiazolidinone, m.p. 137.degree. C.
EXAMPLE 74
5-3-ethoxy-4-hydroxy-5-(methylthiophenyl)phenyl!methylene!-4-oxo-2-thioxo
-3-thiazolidine acetic acid m.p. 202.degree.-206.degree. C.
EXAMPLE 75
5-(1-naphthyl)methylene!-2-thioxo-4-thiazolidinone, m.p.
224.degree.-225.degree. C.
EXAMPLE 76
5-(2-naphthyl)methylmethylene!-2-thioxo-4-thiazolidinone
EXAMPLE 77
5-(3-phenoxyphenyl)methylene!-2-thioxo-4-thiazolidinone
EXAMPLE 78
5-(3-phenoxyphenyl)methylmethylene!-2-thioxo-4-thiazolidinone
EXAMPLE 79
5-3-(methyloxyphenyl)phenyl!methylene!-2-thioxo-4-thiazolidinone, m.p.
177.degree.-180.degree. C.
EXAMPLE 80
5-(3-methoxy-4-heptoxyphenyl)methylene!-2-thioxo-3-amino-4-thiazolidinone,
m.p. 118.degree.-121.degree. C. (dec).
EXAMPLE 81
5-(3-methoxy-4-heptoxyphenyl)methylene!-2-thioxo-3-dimethylamino-4-thiazol
idinone
Two hundred and fifty milligrams (1 mmol) of 3-methoxy-4-heptoxy
benzaldehyde, 233 mg (1.2 mmol) of
2-(N-dimethylamino-dithiocarboxamido)acetic acid (a compound of formula
VI, above), 330 mg (4 mmol) of anhydrous sodium acetate and 5 ml of acetic
acid were stirred while heating at reflux for 15 hours. The reaction was
then quenched by pouring the reaction solution into 10 ml of an ice/water
mixture. The resulting solids were recovered by filtration, washed with
ethyl acetate and then water to provide 450 mg of impure title compound.
The impure compound was purified via recrystallization from
hexane/methylene chloride to provide 180 mg of pure title compound. m.p.
105.degree.-108.degree. C.
EXAMPLE 82
5-4-(dimethylamino)phenyl!methylene!-2-thioxo-4-thiazolidinone
EXAMPLE 83
5-(4-heptoxyphenyl)methylene!-2-thioxo-3-dimethylamino-4-thiazolidinone,
m.p. 80.degree. C.
EXAMPLE 84
5-(3-ethoxy-4-hydroxyphenyl)methylene!-2-thioxo-3-cyclohexyl-4-thiazolidin
one, m.p. 122.degree.-123.degree. C.
EXAMPLE 85
5-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl!methylene!-2-thioxo-3-methyl
-4-thiazolidinone, m.p.>200.degree. C.
EXAMPLE 86
5-(3-methanesulfonamidophenyl)methylene!-4-oxo-2-thioxo-3-thiazolidine
acetic acid, m.p.>230.degree. C.
EXAMPLE 87
5-3,5-bis(1,1-dimethylethyl)-4-methoxyphenyl!methylene!-2-thioxo-4-thiazo
lidinone, m.p. 234.degree.-236.degree. C.
EXAMPLE 88
5-(3-ethoxy-4-hydroxyphenyl)methylene!-2-thioxo-3-methyl-4-thiazolidinone,
m.p. 157.degree. C.
EXAMPLE 89
5-3-ethoxy-4-hydroxy-5-(methylthiophenyl)phenyl!methylene!-2-thioxo-3-dim
ethylamino-4-thiazolidinone, m.p. 137.degree.-141.degree. C.
EXAMPLE 90
5-(3-ethoxy-4-hydroxyphenyl)methylene!-2-thioxo-3-dimethylamino-4-thiazoli
dinone, m.p. 194.degree.-198.degree. C.
EXAMPLE 91
5-(3,4-dipentoxyphenyl)methylene!-4-oxo-2-thioxo-3-thiazolidine acetic
acid, m.p. 179.degree.-182.degree. C.
EXAMPLE 92
5-3-(1,1-dimethylethyl)-4-hydroxyphenyl!methylene!-2-thioxo-3-methyl-4-th
iazolidinone, m.p.>230.degree. C.
EXAMPLE 93
5-(3,4-diheptoxyphenyl)methylene!-2-thioxo-3-dimethylamino-4-thiazolidinon
e, m.p. 67.degree. C.
EXAMPLE 94
5-(3,4-dibutoxyphenyl)methylene!-2-thioxo-3-dimethylamino-4-thiazolidinone
, m.p. 92.degree. C.
EXAMPLE 95
5-(3-methoxy-4-heptoxyphenyl)methylene!-2-thioxo-3-(2-propenyl)-4-thiazoli
dinone, m.p. 75.degree.-78.degree. C.
The present invention provides a method for lowering blood glucose levels
in mammals comprising administering a therapeutically effective amount of
a compound of formula I. The term "therapeutically effective amount", as
defined herein, means the amount of compound necessary to provide a
hypoglycemic effect following administration, preferably to a human
susceptible to adult onset diabetes.
The hypoglycemic activity of the compounds of the present invention was
determined by testing the efficacy of the compounds in vivo in male viable
yellow obese-diabetic mice. The test procedure is described in detail
below.
Test formulations were prepared by dissolving the test compound in a saline
solution containing 2% Emulphor (a polyoxyethylated vegetable oil
surfactant from GAF Corp.) to provide the dose level desired. Each test
formulation was administered to six viable yellow obese-diabetic mice
intraperitoneally at the beginning of the experiment. Blood glucose levels
were determined immediately before the first dose and at 2 and 4 hours
thereafter using glucose oxidase. A mean was taken of the 6 values
obtained before the first dose and at the 2 and 4 hour intervals. The 2
and 4 hour mean values, calculated as a percentage of the first dose mean
value, are reported in Table 1, below. In Table 1, Column 1 provides the
example number of the test compound, Column 2 provides the dose level of
compound tested, and Columns 3 and 4 provide a measurement of the test
animal's blood glucose level 2 and 4 hours after test compound
administration, respectively, as a percentage of the test animal's
pre-administration blood glucose level.
TABLE 1
______________________________________
HYPOGLYCEMIC ACTIVITY OF TEST COMPOUNDS IN
OBESE DIABETIC MICE
Percent of Initial
Example # of Blood Glucose Level
Compound Dose After After
Tested (mg/kg) 2 hrs. 4 hrs.
______________________________________
1 50 82 .+-. 5
75 .+-. 2
2 50 96 .+-. 1
82 .+-. 3
3 50 90 .+-. 10
73 .+-. 3
4 50 91 .+-. 4
72 .+-. 7
5 50 79 .+-. 4
71 .+-. 3
6 50 85 .+-. 6
72 .+-. 4
6 50 92 .+-. 4
79 .+-. 4
7 50 80 .+-. 4
91 .+-. 7
8 50 94 .+-. 4
84 .+-. 6
9 50 91 .+-. 8
83 .+-. 6
10 50 89 .+-. 4
80 .+-. 4
11 50 84 .+-. 3
85 .+-. 6
12 50 90 .+-. 7
69 .+-. 6
13 50 94 .+-. 4
88 .+-. 5
14 50 84 .+-. 7
71 .+-. 8
15 50 73 .+-. 5
62 .+-. 4
16 50 94 .+-. 8
96 .+-. 9
17 50 88 .+-. 8
89 .+-. 10
18 50 89 .+-. 4
88 .+-. 5
19 50 85 .+-. 14
75 .+-. 4
20 50 76 .+-. 3
70 .+-. 5
21 50 99 .+-. 4
81 .+-. 6
22 50 77 .+-. 5
67 .+-. 2
22 50 77 .+-. 6
69 .+-. 6
23 50 74 .+-. 6
90 .+-. 6
24 50 78 .+-. 4
80 .+-. 5
25 50 78 .+-. 4
74 .+-. 4
25 25 84 .+-. 5
87 .+-. 6
26 50 80 .+-. 4
75 .+-. 2
27 50 93 .+-. 3
84 .+-. 6
28 50 83 .+-. 9
79 .+-. 7
29 50 84 .+-. 5
77 .+-. 6
30 50 78 .+-. 7
81 .+-. 5
31 50 76 .+-. 7
76 .+-. 5
32 50 75 .+-. 4
80 .+-. 8
32 50 80 .+-. 18
66 .+-. 11
33 50 91 .+-. 6
86 .+-. 7
34 50 85 .+-. 8
79 .+-. 9
35 50 83 .+-. 5
85 .+-. 6
36 50 81 .+-. 7
90 .+-. 8
37 50 89 .+-. 4
80 .+-. 4
38 50 60 .+-. 5
59 .+-. 4
38 50 96 .+-. 6
80 .+-. 3
38 50 86 .+-. 4
81 .+-. 5
38 25 69 .+-. 9
65 .+-. 7
38 10 72 .+-. 4
71 + 6
38 10 73 .+-. 8
59 .+-. 7
39 50 83 .+-. 4
76 .+-. 4
40 50 78 .+-. 5
72 .+-. 4
41 50 61 .+-. 3
51 .+-. 4
41 50 64 .+-. 6
54 .+-. 5
41 50 77 .+-. 5
62 .+-. 5
41 50 77 .+-. 5
72 .+-. 8
41 25 58 .+-. 6
45 .+-. 5
41 25 72 .+-. 7
64 .+-. 4
41 25 74 .+-. 7
70 .+-. 8
41 25 87 .+-. 5
85 .+-. 6
41 10 80 .+-. 7
59 .+-. 4
41 10 97 .+-. 7
75 .+-. 5
41 10 92 .+-. 7
92 .+-. 7
41 5 93 .+-. 10
71 .+-. 4
41 5 95 .+-. 4
97 .+-.
5
42 50 87 .+-. 8
70 .+-. 8
43 50 92 .+-. 7
88 .+-. 4
44 50 98 .+-. 4
88 .+-. 5
45 50 76 .+-. 7
57 .+-. 3
45 50 68 .+-. 2
66 .+-. 4
45 25 93 .+-. 4
87 .+-. 5
45 25 83 .+-. 10
78 .+-. 12
46 50 79 .+-. 4
77 .+-. 5
47 50 99 .+-. 14
76 .+-. 8
48 50 70 .+-. 3
65 .+-. 3
48 25 87 .+-. 4
81 .+-. 5
49 50 83 .+-. 5
77 .+-. 7
50 50 75 .+-. 5
69 .+-. 5
51 50 89 .+-. 7
85 .+-. 8
52 50 73 .+-. 3
61 .+-. 4
53 100 83 .+-. 9
80 .+-. 14
53 50 73 .+-. 4
55 .+-. 5
54 50 76 .+-. 7
74 .+-. 6
55 50 81 .+-. 3
75 .+-. 3
56 50 78 .+-. 4
72 .+-. 3
56 25 81 .+-. 8
75 .+-. 3
56 10 94 .+-. 4
97 .+-. 4
57 50 63 .+-. 6
58 .+-. 7
57 50 69 .+-. 5
63 .+-. 7
57 25 67 .+-. 7
66 .+-. 7
57 25 79 .+-. 10
70 .+-. 4
57 10 95 .+-. 3
87 .+-. 6
57 5 82 .+-. 6
68 .+-. 5
58 50 67 .+-. 2
75 .+-. 5
59 50 62 .+-. 5
59 .+-. 9
60 50 85 .+-. 4
78 .+-. 3
60 50 102 .+-. 6
81 .+-. 5
60 25 87 .+-. 7
89 .+-. 6
61 50 76 .+-. 5
61 .+-. 5
61 50 98 .+-. 8
79 .+-. 4
______________________________________
The hypoglycemic activity of the compounds of the present invention was
confirmed in a second in vivo test system; namely, the normal fed rat
system. The procedure used in this test system is described below.
Male Sprague Dawley rats (Charles River Laboratories) weighing 175-200 g
were used in this test system. Test formulations were prepared by
suspending the test compound in 5% acacia (concentration of the drug was
adjusted such that 0.25 ml/100 g body weight administered orally gave the
desired dose on a body weight basis). The desired dose level of each test
formulation was administered to four rats by oral gavage at the beginning
of the experiment. Blood glucose levels were determined immediately before
the first dose and at 3 and 5 hours thereafter by an enzymatic procedure
employing glucose oxidase and peroxidase coupled with a chromogenic oxygen
acceptor. A mean was taken of the 4 values obtained before the first dose
and at the 3 and 5 hour intervals. The 3 and 5 hour mean values,
calculated as a percentage of the first dose mean value, are reported in
Table 2, below. In Table 2, Column 1 provides the example number of the
test compound, Column 2 provides the dose level of compound tested, and
Columns 3 and 4 provide a measurement of the test animal's blood glucose
level 3 and 5 hours after test compound administration, respectively, as a
percentage of the test animal's pre-administration blood glucose level.
TABLE 2
______________________________________
HYPOGLYCEMIC ACTIVITY OF TEST COMPOUNDS IN
NORMAL FED RATS
Percent of Initial
Example # of Blood Glucose Level
Compound Dose After After
Tested (mg/kg) 3 hrs. 5 hrs.
______________________________________
15 167 84 87
16 200 92 79
17 200 78 68
22 200 84 68
24 200 100 100
25 200 100 100
26 200 100 100
31 200 95 92
32 200 100 96
38 200 90 74
41 160 76 67
45 167 61 63
47 200 82 73
48 167 87 81
49 200 100 98
56 150 79 65
57 200 84 73
58 200 100 100
61 200 89 82
62 200 78 53
63 200 69 52
64 200 91 89
65 200 100 91
66 200 100 86
67 200 92 88
68 200 88 89
69 200 93 88
______________________________________
The hypoglycemic activity of the compounds of the present invention was
confirmed in yet a third in vivo test system; namely, the obese diabetic
Zucker rat (Zucker Diabetic Fatty Rat) test system. The rats used in this
test system were 6 to 8 months old, weighed between 550 to 625 grams and
had a pre-drug blood glucose level between 250 to 350 mg/dl. The procedure
used in this test system is the same as that described for the normal fed
rat test system, above. The results of such tests are set forth in Table
3, below. The format of Table 3 is the same as that used in Table 2.
TABLE 3
______________________________________
HYPOGLYCEMIC ACTIVITY OF TEST COMPOUNDS IN
OBESE DIABETIC ZUCKER RATS
Percent of Initial
Example # of Blood Glucose Level
Compound Dose After After
Tested (mg/kg) 3 hrs. 5 hrs.
______________________________________
22 50 53 56
45 167 30 20
47 167 74 66
56 50 79 66
______________________________________
Finally, the long-term hypoglycemic activity of the compounds of the
present invention was tested in yet another in vivo test system. This
long-term test system entailed incorporating test compound into the test
animal's diet at various concentrations (control animal's diet contained
no test compound). Such diet was then fed to the test or control animals
for either 14 or 21 days. Each test or control animal was then bled from
the tail (200-400 .mu.l sample of blood) at 0 (before diet started), 7, 14
and, if appropriate, 21 and 28 days after diet administration was started.
Plasma samples were then obtained from each blood sample collected and the
glucose concentration of such plasma samples was determined enzymatically.
The results of the long-term hypoglycemic test system described above are
set forth in Table 4, below. In Table 4, Column 1 describes the type of
rodent used in the test system, Column 2 provides the example number of
the test compound or indicates that the numbers reported are for a control
animal, Column 3 provides the concentration, in percent, of test compound
in the test or control animal's diet. Columns 4-8 provide the plasma
glucose concentration at days 0, 7, 14 and, if appropriate, 21 and 28,
respectively, for the animals tested. Glucose lowering was not associated
with depressed diet consumption.
TABLE 4
__________________________________________________________________________
LONG-TERM HYPOGLYCEMIC ACTIVITY OF TEST COMPOUNDS
Concentration
Plasma Glucose Concentration
Example No. of
of Test Cmpd.
(mg/dl)
Type of Rodent*
Cmpd. Tested
in Diet (%)
0 7 14 21 28
__________________________________________________________________________
ZDF 45 0.1 388
140
155
-- --
ZDF control -- 416
364
445
-- --
ZDF 45 0.1 464
215
238
285
--
ZDF 45 0.025 467
451
452
517
--
ZDF control -- 478
499
571
565
--
ZDF 45 0.1 357
171
166
-- --
ZDF 64 0.1 339
187
182
-- --
ZDF control -- 343
423
454
-- --
ZDF 45 0.1 309
137
142
-- --
ZDF 71 0.1 311
237
232
-- --
ZDF 70 0.1 300
190
195
-- --
ZDF control -- 317
286
255
-- --
Male A.sup.VY /a
45 0.1 438
338
315
287
295
(Harlan)
Male A.sup.vy /a
38 0.1 340
351
328
303
331
(Harlan)
Male A.sup.vy /a
control -- 429
414
410
390
359
(Harlan)
__________________________________________________________________________
*ZDF = 8 week old male Zucker Diabetic Fatty rat; A.sup.vy /.sup.a =
viable yellow mouse
The present invention also provides a method for treating Alzheimer's
disease in mammals comprising administering a therapeutically effective
amount of a compound of formula Ia. The term "therapeutically effective
amount", as defined for this method, means the amount of compound
necessary to reduce, eliminate or prevent the physiological effects or
causes of Alzheimer's disease following administration, preferably to a
human suffering from or susceptible to Alzheimer's disease.
Alzheimer's disease is a degenerative disorder of the human brain.
Clinically, it appears as a progressive dementia. Its histopathology is
characterized by degeneration of neurons, gliosis, and the abnormal
deposition of proteins in the brain. Proteinaceous deposits (called
"amyloid") appear as neurofibrillary tangles, amyloid plaque cores, and
amyloid of the congophilic angiopathy. For reviews, see, Alzheimer's
Disease, (B. Reisberg, ed., The Free Press 1983).!
While there is no general agreement as to the chemical nature of
neurofibrillary tangles, the major constituent of both the amyloid plaque
cores and the amyloid of the congophilic angiopathy has been shown to be a
4500 Dalton protein originally termed .beta.-protein or amyloid A4.
Throughout this document this protein is referred to as .beta.-amyloid
peptide or protein.
.beta.-amyloid peptide is proteolytically derived from a transmembrane
protein, the amyloid precursor protein (APP). Different splice forms of
the amyloid precursor protein are encoded by a widely expressed gene. see,
e.g., K. Beyreuther and B. Muller-Hill, Annual Reviews in Biochemistry,
58:287-307 (1989). .beta.-amyloid peptide consists, in its longest forms,
of 42 or 43 amino acid residues. J. Kang, et al., Nature (London),
325:733-736 (1987). These peptides, however, vary as to their
amino-termini. C. Hilbich, et al., Journal of Molecular Biology,
218:149-163 (1991).
Because senile plaques are invariably surrounded by dystrophic neurites, it
was proposed early that .beta.-amyloid peptide is involved in the loss of
neuronal cells that occurs in Alzheimer's disease. B. Yankner and
co-workers were the first to demonstrate that synthetic .beta.-amyloid
peptide could be neurotoxic in vitro and in vivo. B. A. Yankner, et al.,
Science, 245:417 (1989); see also, N. W. Kowall, et al., Proceedings of
the National Academy of Sciences, U.S.A., 88:7247 (1991). Other research
groups, however, were unable to consistently demonstrate direct toxicity
with .beta.-amyloid peptide. see, e.g., Neurobiology of Aging, 13:535 (K.
Kosik and P. Coleman, eds. 1992). Even groups receiving .beta.-amyloid
peptide from a common source demonstrate conflicting results. D. Price, et
al., Neurobiology of Aging, 13:623-625 (1991) (and the references cited
therein).
As mentioned supra, cells have alternative mechanisms for processing APP
which can result in the formation of the .beta.-amyloid protein and
subsequently, the senile plaques. It is likely that this alternative
processing route occurs in the lysosomes. It has been found that compounds
that inhibit lysosomal enzymes inhibit the fragment formation. see, e.g.,
Science, 155:689 (1992).
A lysosome is a membranous reservoir of hydrolyric enzymes responsible for
the intracellular digestion of macromolecules. Lysosomes are known to
contain approximately forty hydrolyric enzymes, including proteases,
nucleases, glycosidases, lipases, phospholipases, phosphatases and
sulfatases. These enzymese are all acid hydrolases which are optimally
active at about pH 5. Therefore, it is necessary to determine which enzyme
or enzymes are responsible for this alternative processing of the APP and
the consequent formation of the .beta.-amyloid protein.
Abnormally high concentrations of the proteases cathepsins D and B have
been observed in the brains of patients with early-onset Alzheimer's
disease. Yu Nakamura, et al., Neuroscience Letters, 130, 195-198 (1991).
Furthermore, elevated activity for cathepsin D has been observed in the
brains of Alzheimer's patients. M. Takeda, et al., Neurochemistry
Research, (abstract), 11:117 (1986). Cathepsin D is a lysosomal
endoprotease that is present in all mammalian cells. see, e.g.,
"Proteinases in Mammalian Cells and Tissues," ed. (A. J. Barret, ed. 1977)
pp. 209-248. It is the only aspartyl protease that is known to be a
lysosomal enzyme.
The cathepsins are a family of hydrolase enzymes that are usually located
in the lysosomes. These enzymes are endopeptidases with an acidic optimum
pH. Cathepsin A is a serine carboxypeptidase, cathepsin C EC 3.4.14.1! is
a dipeptidyl peptidase, cathepsin D EC 3.4.23.5! is an aspartyl protease,
and cathepsin B.sub.2 EC 3.4.16.1! is a serine carboxypeptidase.
Cathepsin B EC 3.4.22.1! (also known as cathepsin B.sub.1) and cathepsin
L EC 3.4.22.15! are thiol proteases having activity within the lysosomes.
It has been found that inhibition of cathepsin D using an aspartyl protease
inhibitor reduces the formation of .beta.-amyloid protein and the
resultant senile plaque. As such, compounds which inhibit cathepsins (and,
in particular, cathepsin D) or reduce the formation of .beta.-amyloid
protein would be expected to be useful in treating Alzheimer's disease.
Such activities were demonstrated in the following test systems.
CATHEPSIN D PERCENT INHIBITION ACTIVITY
A fluorometric assay was adapted from the method disclosed by Murakami et
al., Anal, Biochem. 110:232-239 (1981) for measuring renin activity. Human
liver cathepsin D (Athens Research and Technology, Athens, Ga.) was
diluted in assay buffer, 200 mM NaOAc, pH 4.5, 150 mM NaCl to 500 ng/mL
and then 100 .mu.L of this cathepsin D solution was added to each well of
a 96 well plate with the exception of control wells which received just
100 .mu.L of assay buffer. Compound stocks were prepared by dissolving a
sufficient quantity of the particular compound to be tested in DMSO such
that various concentrations (either 10 .mu.g/ml, 8.3 .mu.g/ml or 4.15
.mu.g/ml) of test compound in DMSO were obtained and then 5 .mu.L of the
compound stock was added to each of the wells prepared above. Blank and
enzyme control wells each received 5 .mu.L of the DMSO vehicle.
Following a ten minute incubation at 25.degree. C. to allow enzyme/compound
interaction, 5 .mu.L of a 500 .mu.M solution of a derivative of a known
porcine renin tetradecapeptide fluorometric substrate (Bachem Biosciences,
Inc. 1993 Catalog ID No. I-1340; Bachem Biosciences, Philadelphia, Pa.) in
DMSO was added per well to initiate the reaction. After incubation at
37.degree. C. for 30 minutes, cathepsin D activity was terminated by the
addition of 100 .mu.L per well of 400 mU/mL microsomal leucine
aminopeptidase (EC 3.4.11.2, Sigma, St. Louis, Mo.) in 1M Tris-HCl, pH
8.0.
The plates were then analyzed in a fluorometer (CytoFluor 2350, Millipore,
Bedford, Mass.) with an excitation wavelength of 360 nm and an emission
wavelength of 460 nm, in order to check for background fluorescence due to
test compounds. Following a two hour incubation at 37.degree. C., to allow
the aminopeptidase to release the fluorophore, 7-amido-4-methylcoumarin
(AMC) from the products of cathepsin D cleavage, the plates were again
analyzed in the fluorometer. In order to check for potential false
positives, i.e., inhibitors of microsomal leucine aminopeptidase, residual
aminopeptidase activity was monitored directly in each well by the
addition of 20 .mu.L/well of 2.5 mM Leu-pNA (Bachem Biosciences,
Philadelphia, Pa.) in 10% DMSO. Aminopeptidase activity was measured as an
increase in the absorbance of 405 nm in a UV.sub.max microplate reader
(Molecular Devices, Menlo Park, Calif.).
Cathepsin D activity was linear under these conditions and the results are
expressed as a percentage of the controls in Table 5, below. All results
presented are the mean and standard deviation of at least four replicate
assays.
TABLE 5
______________________________________
CATHEPSIN D INHIBITION ACTIVITY
Compound Stock
Concentration
% Inhibition
Example No. (.mu.g/ml) of Cathepsin D
______________________________________
1 10.0 36
4 10.0 50
5 10.0 76
5 8.3 100
6 10.0 29
8 10.0 64
18 10.0 38
21 4.15 40
31 10.0 88.5
31 4.15 69.5
32 4.15 75
35 4.15 57
42 10.0 87.5
42 4.15 78
45 8.3 95
45 4.15 49.5
47 4.15 60.5
50 4.15 40
55 4.15 90
56 4.15 73
60 8.3 38
60 4.15 45.5
63 4.15 53
68 4.15 53.7
69 4.15 51
70 4.15 66
71 10.0 76
71 8.3 94
72 8.3 96
72 4.15 88
73 8.3 76
73 4.15 69
74 8.3 95
75 10.0 43
76 10.0 32
77 10.0 87
77 4.15 64
78 4.15 41
79 4.15 87
80 8.3 33
81 8.3 21
82 10.0 73.5
83 4.15 47
34 4.15 51
86 8.3 42
88 8.3 82
88 4.15 67
89 8.3 71
90 8.3 92
90 4.15 79
91 4.15 72
92 4.15 74
94 4.15 48
95 8.3 36
______________________________________
CATHEPSIN D INHIBITION IC.sub.50 ACTIVITY
The above assay was repeated with the exception that the compound stocks
were prepared in concentrations such that IC.sub.50 values (concentration
of test compound at which 50% inhibition of cathepsin D was obtained) for
the test compounds could be determined. The results obtained from such
assay system are set forth in Table 6 below.
TABLE 6
______________________________________
Example No. IC.sub.50 (.mu.M)
______________________________________
5 3.6
28 3.1
31 1.9
35 8.9
42 1.7
47 5.2
56 12.3
60 14.75
68 10.2
69 2.1
70 5.4
71 2.1
72 1.7
73 9.9
74 5.8
77 3.7
78 22.1
79 3.7
80 47.0
81 319.4
85 14.3
87 2.2
88 11.2
89 9.2
90 7.7
91 9.7
92 3.9
93 7.5
______________________________________
.beta.-AMYLOID PROTEIN PRODUCTION INHIBITION
Two cell lines (human kidney cell line 293 and Chinese hamster ovary cell
line CHO) were stably transfected with the gene for APP751 containing the
double mutation Lys-651-Met-652 to Asn-651-Leu-652 (APP-751 numbering)
commonly called the Swedish mutation using the method described in Citron
et al., Nature 360:672-674 (1992). The transfected cell lines were
designated as 293 751 SWE and CHO 751 SWE, and were plated in Corning 96
well plates at 2.5.times.10.sup.4 or 1.times.10.sup.4 cells per well
respectively in Dulbecco's minimal essential media (DMEM) plus 10% fetal
bovine serum. Following overnight incubation at 37.degree. C. in an
incubator equilibrated with 10% carbon dioxide (CO.sub.2), the media were
removed and replaced with 200 .mu.L per well of conditioned media (media
containing compound stocks; compound stocks diluted with media such that
the concentration of DMSO in the media/compound stock solution did not
exceed 0.5%) for a two hour pretreatment period during which the cells
were incubated as described above. These compound stocks were prepared by
dissolving a sufficient quantity of the particular compound to be tested
in DMSO such that various concentrations were obtained. After this
pretreatment period, the conditioned media was removed and replaced with
fresh conditioned media and the cells were incubated for an additional two
hours.
After treatment, plates were centrifuged in a Beckman GPR at 1200 rpm for
five minutes at room temperature to pellet cellular debris from the
conditioned media. From each well, 100 .mu.L of conditioned media were
transferred into an ELISA plate precoated with antibody 266 Seubert et
al., Nature, 359:325-327 (1992)! and stored at 4.degree. C. overnight
prior to the completion of the ELISA assay the next day.
Cytotoxic effects of the compounds were measured by a modification of the
method of Hansen et al., J. Immun. Meth. 119:203-210 (1989). To the cells
remaining in the tissue culture plate, was added 25 .mu.L of a
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) stock
solution (5 mg/mL) to a final concentration of 1 mg/mL. Cells vere
incubated at 37.degree. C. for one hour, and cellular activity was stopped
by the addition of an equal volume of MTT lysis buffer (20% w/v sodium
dodecylsulfate in 50% DMF, pH 4.7). Complete extraction was achieved by
overnight shaking at room temperature. The difference in the OD.sub.562 nm
and the OD.sub.650 nm was measured in a Molecular Devices UV.sub.max
microplate reader as an indicator of the cellular viability.
The results of the .beta.-amyloid protein ELISA were fit to a standard
curve and expressed as ng/mL .beta.-amyloid protein peptide. In order to
normalize for cytotoxicity, these .beta.-amyloid protein results were
divided by the cytotoxicity results and expressed as a percentage of the
results from a drug-free control.
TABLE 7
______________________________________
.beta.-AMYLOID PROTEIN INHIBITION
Compound Stock
Concentration
% Inhibition of
Example No. (.mu.g/ml) .beta.-Amyloid Protein
______________________________________
5 10.0 47
31 10.0 57
31 5.0 37
31 2.5 28
31 1.25 15
31 0.62 7
31 0.31 0
42 10.0 51
42 5.0 35
42 2.5 16
42 1.25 14
42 0.62 11
42 0.31 8
70 10.0 38
71 10.0 65
77 10.0 25
81 10.0 100
______________________________________
As can be seen from the data in Tables 5, 6 and 7, the compounds of formula
Ia can be administered for prophylactic and/or therapeutic treatment of
diseases related to the deposition of .beta.-amyloid protein such as
Alzheimer's disease, Down's syndrome, and advanced aging of the brain. In
therapeutic applications, the compounds are administered to a host already
suffering from the disease. The compounds will be administered in an
amount sufficient to inhibit further deposition of .beta.-amyloid protein
plaque.
For prophylactic applications, the compounds of formula Ia are administered
to a host susceptible to Alzheimer's disease or a .beta.-amyloid protein
related disease, but not already suffering from such disease. Such hosts
may be identified by genetic screening and clinical analysis, as described
in the medical literature. see e.g., Goate, Nature 349:704-706 (1991). The
compounds will be able to inhibit or prevent the formation of the
.beta.-amyloid protein plaque at a symptomatically early stage, preferably
preventing even the initial stages of the .beta.-amyloid protein disease.
The compounds of the present invention and the compounds utilized in the
methods of the present invention are effective over a wide dosage range.
For example, dosages per day will normally fall within the range of about
0.5 to about 500 mg/kg of body weight. In the treatment of adult humans,
the range of about 1.0 to about 100 mg/kg, in single or divided doses, is
preferred. However, it will be understood that the amount of the compound
actually administered will be determined by a physician in light of the
relevant circumstances including the condition to be treated, the choice
of compound to be administered, the age, weight, and response of the
individual patient, the severity of the patient's symptoms and the chosen
route of administration. Therefore, the above dosage ranges are not
intended to limit the scope of the invention in any way. While the present
compounds are preferably administered orally, the compounds may also be
administered by a variety of other routes such as the transdermal,
subcutaneous, intranasal, intramuscular and intravenous routes.
While it is possible to administer a compound of the invention, or a
compound used in the methods of this invention, directly, the compounds
are preferably employed in the form of a pharmaceutical formulation
comprising a pharmaceutically acceptable carrier, diluent or excipient and
a compound of the invention. Such formulations will contain from about
0.01 percent to about 90 percent of a compound of the invention.
In making the formulations of the present invention, the active ingredient
will usually be mixed with at least one carrier, or diluted by at least
one carrier, or enclosed within a carrier which may be in the form of a
capsule, sachet, paper or other container. When the carrier serves as a
diluent, it may be a solid, semi-solid or liquid material which acts as a
vehicle, excipient or medium for the active ingredient. Thus, the
formulations can be in the form of tablets, granules, pills, powders,
lozenges, sachets, cachets, elixirs, emulsions, solutions, syrups,
suspensions, aerosols (as a solid or in a liquid medium) and soft and hard
gelatin capsules.
Examples of suitable carriers, diluents and excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium
phosphate, alginates, liquid paraffin, calcium silicate, microcrystalline
cellulose, polyvinyl pyrrolidone, cellulose, tragacanth, gelatin, syrup,
methyl cellulose, methyl- and propyl-hydroxybenzoates, vegetable oils,
such as olive oil, injectable organic esters such as ethyl oleate, talc,
magnesium stearate, water and mineral oil. The formulations may also
include wetting agents, lubricating, emulsifying and suspending agents,
preserving agents, sweetening agents, perfuming agents, stabilizing agents
or flavoring agents. The formulations of the invention may be formulated
so as to provide quick, sustained or delayed release of the active
ingredient after administration to the patient by employing procedures
well-known in the art.
For oral administration, a compound of this invention, or a compound used
in the methods of this invention, ideally can be admixed with carriers and
diluents and molded into tablets or enclosed in gelatin capsules.
The compositions are preferably formulated in a unit dosage form, each
dosage containing from about 1 to about 500 mg, more usually about 5 to
about 300 mg, of the active ingredient. The term "unit dosage form" refers
to physically discrete units suitable as unitary dosages for human
subjects and other mammals, each unit containing a predetermined quantity
of active material calculated to produce the desired therapeutic effect,
in association with a suitable pharmaceutical carrier, diluent or
excipient therefor.
In order to more fully illustrate the operation of this invention, the
following examples of formulations are provided. The examples are
illustrative only and are not intended to limit the scope of the
invention. The formulations may employ as active compounds any of the
compounds of the present invention.
FORMULATION 1
Hard gelatin capsules suitable for use in treating Alzheimer's disease or
reducing glucose concentration are prepared using the following
ingredients:
______________________________________
Amt. per
Concentration by
Capsule
Weight (percent)
______________________________________
Compound of Example No. 5
250 mg 55.0
Starch dried 220 mg 43.0
Magnesium stearate
10 mg 2.0
460 mg 100.0
______________________________________
The above ingredients are mixed and filled into hard gelatin capsules in
460 mg quantities.
FORMULATION 2
Capsules each containing 20 mg of medicament are made as follows:
______________________________________
Amt. per
Concentration by
Capsule
Weight (percent)
______________________________________
Compound of Example No. 1
20 mg 10.0
Starch 89 mg 44.5
Microcrystalline 89 mg 44.5
cellulose
Magnesium stearate
2 mg 1.0
200 mg 100.0
______________________________________
The active ingredient, cellulose, starch and magnesium stearate are
blended, passed through a No. 45 mesh U.S. sieve and filled into a hard
gelatin capsule.
FORMULATION 3
Capsules each containing 100 mg of active ingredient are made as follows:
______________________________________
Amt. per
Concentration by
Capsule
Weight (percent)
______________________________________
Compound of Example No. 45
100 mg 29.0
Polyoxyethylenesorbitan
50 mcg 0.02
monooleate
Starch powder 250 mg 71.0
250.05 mg
100.02
______________________________________
The above ingredients are thoroughly mixed and placed in an empty gelatin
capsule.
FORMULATION 4
Tablets each containing 10 mg of active ingredient are made up as follows:
______________________________________
Amt. per
Concentration by
Capsule
Weight (percent)
______________________________________
Compound of Example No. 71
10 mg 10.0
Starch 45 mg 45.0
Microcrystalline 35 mg 35.0
cellulose
Polyvinyl 4 mg 4.0
pyrrolidone (as 10%
solution in water)
Sodium carboxyethyl
4.5 mg 4.5
starch
Magnesium stearate 0.5 mg 0.5
Talc 1 mg 1.0
100 mg 100.0
______________________________________
The active ingredient, starch and cellulose are passed through a No. 45
mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone
is mixed with the resultant powders which are then passed through a No. 14
mesh U.S. sieve. The granule so produced is dried at 50.degree.-60.degree.
C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl
starch, magnesium stearate and talc, previously passed through a No. 60
mesh U.S. sieve, are then added to the granule which, after mixing, is
compressed on a tablet machine to yield a tablet weighing 100 mg.
FORMULATION 5
A tablet formula may be prepared using the ingredients below:
______________________________________
Amt. per
Concentration by
Capsule
Weight (percent)
______________________________________
Compound of Example No. 2
250 mg 38.0
Cellulose 400 mg 60.0
microcrystalline
Silicon dioxide 10 mg 1.5
fumed
Stearic acid 5 mg 0.5
665 mg 100.0
______________________________________
The components are blended and compressed to form tablets each weighing 665
mg.
FORMULATION 6
Suspensions each containing 5 mg of medicament per 40 ml dose are made as
follows:
______________________________________
Per 5 ml of suspension
______________________________________
Compound of Example No. 59
5 mg
Sodium carboxymethyl 50 mg
cellulose
Syrup 1.25 ml
Benzoic acid solution
0.10 ml
Flavor q.v.
Color q.v.
Water q.s. to 5 ml
______________________________________
The medicament is passed through a No. 45 mesh U.S. sieve and mixed with
the sodium carboxymethylcellulose and syrup to form a smooth paste. The
benzoic acid solution, flavor and color is diluted with some of the water
and added, with stirring. Sufficient water is then added to produce the
required volume.
FORMULATION 7
An aerosol solution is prepared containing the following components:
______________________________________
Concentration by Weight (%)
______________________________________
Compound of Example No. 53
0.25
Ethanol 29.75
Propellant 22 70.00
(Chlorodifluoromethane)
100.00
______________________________________
The active compound is mixed with ethanol and the mixture added to a
portion of the propellant 22, cooled to -30.degree. C. and transferred to
a filling device. The required amount is then fed to a stainless steel
container and diluted further with the remaining amount of propellant. The
valve units are then fitted to the container.
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